Analyte sensor

ABSTRACT

The present invention relates generally to systems and methods for measuring an analyte in a host. More particularly, the present invention relates to systems and methods for transcutaneous measurement of glucose in a host.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.11/360,252 filed Feb. 22, 2006, which is a continuation-in-part of U.S.application Ser. No. 11/157,746 filed Jun. 21, 2005, which claimspriority under 35 U.S.C. § 119(e) to U.S. Provisional Application No.60/587,787 filed Jul. 13, 2004; U.S. Provisional Application No.60/587,800 filed Jul. 13, 2004; U.S. Provisional Application No.60/614,683 filed Sep. 30, 2004; and U.S. Provisional Application No.60/614,764 filed Sep. 30, 2004, each of which is hereby expresslyincorporated by reference herein in its entirety, and each of which ishereby made a part of this specification.

FIELD OF THE INVENTION

The present invention relates generally to systems and methods formeasuring an analyte in a host. More particularly, the present inventionrelates to systems and methods for transcutaneous measurement of glucosein a host.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a disorder in which the pancreas cannot createsufficient insulin (Type I or insulin dependent) and/or in which insulinis not effective (Type 2 or non-insulin dependent). In the diabeticstate, the victim suffers from high blood sugar, which can cause anarray of physiological derangements associated with the deterioration ofsmall blood vessels, for example, kidney failure, skin ulcers, orbleeding into the vitreous of the eye. A hypoglycemic reaction (lowblood sugar) can be induced by an inadvertent overdose of insulin, orafter a normal dose of insulin or glucose-lowering agent accompanied byextraordinary exercise or insufficient food intake.

Conventionally, a person with diabetes carries a self-monitoring bloodglucose (SMBG) monitor, which typically requires uncomfortable fingerpricking methods. Due to the lack of comfort and convenience, a personwith diabetes normally only measures his or her glucose levels two tofour times per day. Unfortunately, such time intervals are so far spreadapart that the person with diabetes likely finds out too late of ahyperglycemic or hypoglycemic condition, sometimes incurring dangerousside effects. It is not only unlikely that a person with diabetes willtake a timely SMBG value, it is also likely that he or she will not knowif his or her blood glucose value is going up (higher) or down (lower)based on conventional method. This inhibits the ability to make educatedinsulin therapy decisions.

A variety of sensors are known that use an electrochemical cell toprovide output signals by which the presence or absence of an analyte,such as glucose, in a sample can be determined. For example, in anelectrochemical cell, an analyte (or a species derived from it) that iselectro-active generates a detectable signal at an electrode, and thissignal can be used to detect or measure the presence and/or amountwithin a biological sample. In some conventional sensors, an enzyme isprovided that reacts with the analyte to be measured, and the byproductof the reaction is qualified or quantified at the electrode. An enzymehas the advantage that it can be very specific to an analyte and also,when the analyte itself is not sufficiently electro-active, can be usedto interact with the analyte to generate another species which iselectro-active and to which the sensor can produce a desired output. Inone conventional amperometric glucose oxidase-based glucose sensor,immobilized glucose oxidase catalyses the oxidation of glucose to formhydrogen peroxide, which is then quantified by amperometric measurement(for example, change in electrical current) through a polarizedelectrode.

SUMMARY OF THE INVENTION

In a first aspect, a sensor for transcutaneous measurement of an analytein a host is provided, the sensor comprising at least one electrodeformed from a conductive material; and a membrane disposed on anelectroactive portion of the electrode, wherein the membrane isconfigured to control an influx of the analyte therethrough, and whereinthe membrane comprises a substantially non-smooth outer surface.

In an embodiment of the first aspect, the substantially non-smoothsurface appears under magnification to resemble a super-positioning ofdisc shaped objects.

In an embodiment of the first aspect, the disc shaped objects comprise arounded shape.

In an embodiment of the first aspect, the disc shaped objects have anaverage diameter of from about 5 microns to about 250 microns.

In an embodiment of the first aspect, the membrane further comprises anenzyme domain.

In an embodiment of the first aspect, the membrane further comprises aninterference domain.

In an embodiment of the first aspect, the membrane further comprises anelectrode domain.

In an embodiment of the first aspect, the membrane is at least partiallyformed by a vapor deposition coating process.

In an embodiment of the first aspect, the vapor deposition coatingprocess comprises a physical vapor deposition coating process, e.g.,ultrasonic vapor deposition.

In an embodiment of the first aspect, the membrane substantially resistsascorbate flux therethrough.

In an embodiment of the first aspect, the electrode comprises a wirecomprising a conductive material, and wherein the sensor is configuredfor substantially continuous measurement of glucose in a host.

In a second aspect, a method for manufacturing a transcutaneous analytesensor is provided, the method comprising the steps of providing atleast one electrode comprising an electroactive portion; and applying amembrane to the electroactive port ion, wherein at least one layer ofthe membrane is applied by vapor deposition.

In an embodiment of the second aspect, the vapor deposition comprisesphysical vapor deposition.

In an embodiment of the second aspect, the physical vapor depositioncomprises ultrasonic vapor deposition.

In an embodiment of the second aspect, the layer of the membrane isdeposited in a vacuum chamber. The layer can be configured to resistflow of the analyte therethrough.

In an embodiment of the second aspect, at least one layer of themembrane is applied using an ultrasonic nozzle. The layer can beconfigured to resist flow of the analyte therethrough.

In an embodiment of the second aspect, the step of applying a membranecomprises applying an enzyme domain. The enzyme domain can be applied bydip coating.

In an embodiment of the second aspect, the step of applying a membranecomprises applying an electrode domain. The electrode domain can beapplied by dip coating.

In an embodiment of the second aspect, the electrode comprises a wirecomprising a conductive material, and wherein the sensor is configuredfor substantially continuous measurement of glucose in a host.

In a third aspect, a method for manufacturing a plurality oftranscutaneous analyte sensors is provided, the method comprisingproviding a plurality of electrodes, each electrode comprising anelectroactive portion; placing the plurality of electrodes into a vacuumchamber; and vapor depositing at least one membrane layer thereon.

In an embodiment of the third aspect, the membrane layer is configuredto control influx of an analyte therethrough.

In an embodiment of the third aspect, an in vitro sensitivity of theplurality of sensors deviates from a median in vitro sensitivity by lessabout 20%.

In an embodiment of the third aspect, an in vitro sensitivity of theplurality of sensors deviates from a median in vitro sensitivity by lessabout 16%.

In an embodiment of the third aspect, an in vitro sensitivity of theplurality of sensors deviates from a median in vitro sensitivity by lessabout 12%.

In an embodiment of the third aspect, the method further comprisescuring the membrane layer. The curing step can include placing aplurality of electrodes, each comprising the membrane layer, into avacuum oven, a convection oven, or a variable frequency microwave oven.

In an embodiment of the third aspect, each electrode comprises a wirecomprising a conductive material, and wherein each sensor is configuredfor substantially continuous measurement of glucose in a host.

In a fourth aspect, a method for limiting use of an analyte sensor to apredetermined time period is provided, the method comprising providing akey associated with an analyte sensor, wherein the key is configured tocontrol an amount of time over which information is obtained from theanalyte sensor.

In an embodiment of the fourth aspect, the analyte sensor is atranscutaneous glucose sensor.

In an embodiment of the fourth aspect, the sensor is operativelyconnected to a receiver, wherein the receiver is configured to displaysensor data.

In an embodiment of the fourth aspect, the receiver is configured toreceive the key.

In an embodiment of the fourth aspect, the receiver is configured tocontrol an amount of time over which information is displayed on thereceiver from the sensor in response to the key.

In an embodiment of the fourth aspect, the key is a software key.

In an embodiment of the fourth aspect, the key is a unique code.

In an embodiment of the fourth aspect, the key is selected from thegroup consisting of a unique number, a receiver ID, a sensor duration, anumber of sensor systems, and combinations thereof.

In an embodiment of the fourth aspect, the key is configured for usewith a plurality of sensors.

In an embodiment of the fourth aspect, the key is provided by aninformation tag.

In a fifth aspect, a method for distributing and controlling use ofimplantable sensor systems comprising reusable and disposable parts, themethod comprising providing a single-use device associated with thesensor system, wherein the single-use device is configured to beinserted into a host's tissue; providing a key associated with thesingle-use device; and providing a reusable device associated with asensor system, wherein the reusable device is configured to providesensor information responsive to receipt of the key.

In an embodiment of the fifth aspect, the reusable device comprises areceiver configured to receive sensor information.

In an embodiment of the fifth aspect, the reusable device furthercomprises an electronics unit configured to releasably mate with thesingle-use device.

In an embodiment of the fifth aspect, the method further comprisesobtaining a package containing a plurality of single-use devices.

In an embodiment of the fifth aspect, the single-use device is atranscutaneous analyte sensor configured for insertion into asubcutaneous tissue of a host.

In an embodiment of the fifth aspect, the key comprises a writtenlicense code packaged with the single-use device.

In an embodiment of the fifth aspect, the step of providing the keycomprises providing a license code via at least one communicationselected from the group consisting of written communication, voicecommunication, and electronic communication.

In an embodiment of the fifth aspect, the reusable device is configuredto receive the key via manual entry.

In an embodiment of the fifth aspect, the reusable device is configuredto wirelessly receive the key.

In an embodiment of the fifth aspect, key comprises sensor durationinformation configured to enable the sensor system to control an amountof time over which information is obtained from the single-use device oris displayed by the reusable device.

In an embodiment of the fifth aspect, the single-use device comprises atranscutaneous analyte sensor configured for insertion in a subcutaneoustissue of a host, and wherein the key comprises sensor insertioninformation configured to enable the sensor system to control a numberof sensor insertions.

In an embodiment of the fifth aspect, the single-use device comprises atranscutaneous analyte sensor configured for insertion in a subcutaneoustissue of a host, and wherein the step of inserting the single-usedevice into a host comprises using an applicator to insert the sensorinto the host.

In an embodiment of the fifth aspect, the step of obtaining sensorinformation from the sensor system comprises at least one step selectedfrom the group consisting of measurement of analyte information,digitalizing of sensor information, transmission of sensor information,receiving of sensor information, storing of sensor information,processing of sensor information, and displaying of sensor information.

In a sixth aspect, a method for limiting use of a glucose sensor systemto a predetermined time period is provided, the method comprisinginputting a key into a receiver, wherein the key is configured tocontrol an amount of time over which information is obtained from asensor system, after which time the sensor system is disabled such thatglucose information cannot be obtained, wherein the sensor system is atranscutaneous glucose sensor system comprising a sensor configured forinsertion into a tissue of a host and an electronics unit operativelyconnected to the sensor and configured to provide a signalrepresentative of a glucose concentration in the host, and wherein thereceiver is configured to receive the signal representative of a glucoseconcentration in the host and to display corresponding glucoseinformation; and obtaining glucose information from the sensor.

In an embodiment of the sixth aspect, the step of inputting the key intothe receiver is performed before the step of obtaining glucoseinformation from the sensor.

In a seventh aspect, a device for measuring an analyte in a host isprovided, the device comprising a sensor operably connected to sensorelectronics, the sensor electronics configured for measuring an analytein a host; at least one electrical contact configured to connect thesensor to the sensor electronics; and a sealing member, wherein thesealing member at least partially surrounds at least one of the sensorand the electrical contact, wherein the sealing member comprises amaterial having a durometer hardness of from about 5 Shore A to about 80Shore A.

In an embodiment of the seventh aspect, the durometer hardness is fromabout 10 Shore A to about 50 Shore A.

In an embodiment of the seventh aspect, the durometer hardness is about20 Shore A.

In an embodiment of the seventh aspect, the durometer hardness is about50 Shore A

In an embodiment of the seventh aspect, the sensor comprises a wire.

In an embodiment of the seventh aspect, the sensor comprises a planarsubstrate.

In an embodiment of the seventh aspect, the sealing material comprises asilicone.

In an embodiment of the seventh aspect, the device further comprises asealant adjacent to the sealing member.

In an embodiment of the seventh aspect, the sensor electronics arehoused within an electronics unit configured to mate with the electricalcontact.

In an embodiment of the seventh aspect, the electronics unit and thesealing member are configured to mate to provide a compression forcetherebetween.

In an embodiment of the seventh aspect, the device further comprises atleast one raised portion configured to provide a compression force tothe sealing member when the electrical contact is connected to thesensor electronics.

In an eighth embodiment, a device for use in measuring an analyte in ahost is provided, the device comprising a sensor operably connected tosensor electronics, the sensor electronics configured for measuring ananalyte in a host; at least one electrical contact configured tooperably connect the sensor to the sensor electronics; and a sealingmember at least partially surrounding at least one of the sensor and theelectrical contact, wherein the sealing member is configured to seal theelectrical contact from moisture when the sensor is operably connectedto the sensor electronics.

In an embodiment of the eighth aspect, the sealing member comprises amaterial having a durometer hardness of from about 5 Shore A to about 80Shore A.

In an embodiment of the eighth aspect, the device further comprises asealant adjacent to the sealing member.

In an embodiment of the eighth aspect, the device further comprises ahousing on which the sealing member is disposed, wherein the housing isconfigured to mechanically or chemically hold the sealing memberthereon.

In an embodiment of the eighth aspect, the device further comprises anadhesive configured to hold the sealing member on the housing.

In an embodiment of the eighth aspect, the device further comprises atleast one protrusion configured to substantially mate with at least onedepression, whereby the sealing member is held on the housing.

In an embodiment of the eighth aspect, the sealing member comprises atleast one gap that is maintained when the electrical contact is operablyconnected to the sensor electronics.

In an embodiment of the eighth aspect, the sensor at least partiallyextends through the gap.

In an embodiment of the eighth aspect, the gap is filled with a sealant.

In an embodiment of the eighth aspect, the device further comprises atleast one channel communicating between a first side of the sealingmember and a second side of the sealing member.

In an embodiment of the eighth aspect, the channel is filled with asealant.

In an embodiment of the eighth aspect, substantially no air gaps areadjacent to the electrical contact when the electrical contact isoperably connected to the sensor electronics.

In an embodiment of the eighth aspect, the sealing member comprises amaterial selected from the group consisting of silicone,silicone/polyurethane hybrid, polyurethane, polysulfide, and mixturesthereof.

In an embodiment of the eighth aspect, the sealing member isself-lubricating.

In an embodiment of the eighth aspect, the sealing member comprises asealant sandwiched between an upper portion of the sealing member and alower portion of the sealing member.

In an embodiment of the eighth aspect, the device further comprises aguide tube configured to maintain an opening in the sealing member priorto sensor insertion into the host.

In an embodiment of the eighth aspect, the device further comprises alubricant between the sealing member and the guide tube.

In a ninth aspect, a device for use in measuring an analyte in a host isprovided, the device comprising a sensor operably connected to sensorelectronics, the sensor electronics configured for measuring an analytein a host; at least one electrical contact configured to connect thesensor to the sensor electronics, wherein the electrical contactcomprises a material having a durometer hardness of from about 5 Shore Ato about 80 Shore A; and a sealing member at least partially surroundingat least one of the sensor and the electrical contact, wherein thesealing member comprises a material having a durometer hardness of fromabout 5 Shore A to about 80 Shore A.

In an embodiment of the ninth aspect, the durometer hardness of theelectrical contact is higher than the durometer hardness of the sealingmember.

In an embodiment of the ninth aspect, the durometer hardness of theelectrical contact is about 50 Shore A.

In an embodiment of the ninth aspect, the durometer hardness of thesealing member is higher than the durometer hardness of the contact.

In an embodiment of the ninth aspect, the durometer hardness of thesealing member is about 50 Shore A.

In an embodiment of the ninth aspect, the sealing member comprises afiller material.

In an embodiment of the ninth aspect, the filler material is configuredto stiffen the sealing member.

In a tenth aspect, a sensor system for measuring an analyteconcentration in a host is provided, the system comprising at least oneelectrode configured for implantation in a host and configured tomeasure an analyte concentration in a tissue of the host; sensorelectronics operably connected to the electrode and configured toprovide analyte data representative of an analyte concentration in thehost; and an information tag comprising sensor information.

In an embodiment of the tenth aspect, the information tag comprises amemory.

In an embodiment of the tenth aspect, the information tag transmitsinformation using at least one connection selected from the groupconsisting of a serial connection, a radio frequency connection, anacoustic frequency connection, an infrared frequency connection, and amagnetic induction connection.

In an embodiment of the tenth aspect, the system further comprises amounting unit configured to maintain the sensor positionedtranscutaneously within the tissue of the host.

In an embodiment of the tenth aspect, the information tag is embeddedwithin the mounting unit.

In an embodiment of the tenth aspect, the system further comprises areceiver configured to receive the analyte data from the sensorelectronics.

In an embodiment of the tenth aspect, the receiver is configured to readsensor information from the information tag.

In an embodiment of the tenth aspect, the system further comprisespackaging configured to contain at least a portion of a sensor systemduring transport.

In an embodiment of the tenth aspect, the information tag is in or onthe packaging.

In an embodiment of the tenth aspect, the sensor information comprisesat least one item selected from the group consisting of manufacturinginformation, calibration information, identification information,expiration information, sensor duration information, and archived data.

In an embodiment of the tenth aspect, the sensor information comprises alicense code.

In an eleventh aspect, a transcutaneous analyte sensor assembly isprovided, the assembly comprising a mounting unit adapted for mountingon a skin of a host; an electronics unit configured to releasably matewith the mounting unit; a sensor configured to measure a concentrationof an analyte in the host, wherein the sensor is operably connected tothe electronics unit when the electronics unit is mated to the mountingunit; and an information tag comprising sensor information.

In an embodiment of the eleventh aspect, the sensor information isembedded in an information tag within the mounting unit.

In an embodiment of the eleventh aspect, the assembly further comprisesa receiver, wherein the receiver is configured to read sensorinformation from the information tag.

In an embodiment of the eleventh aspect, the information tag comprises amemory.

In an embodiment of the eleventh aspect, the information tag transmitsinformation using at least one connection selected from the groupconsisting of a serial connection, a radio frequency connection, anacoustic frequency connection, an infrared frequency connection, and amagnetic induction connection.

In an embodiment of the eleventh aspect, the sensor information isembedded within the electronics unit.

In an embodiment of the eleventh aspect, the assembly further comprisespackaging configured to contain the sensor assembly during transport,wherein the information tag is provided in or on the packaging.

In an embodiment of the eleventh aspect, the assembly further comprisesa receiver, wherein the receiver is configured to read the sensorinformation from the information tag.

In an embodiment of the eleventh aspect, the sensor informationcomprises information configured to trigger initialization of thesensor.

In a twelfth aspect, a transcutaneous glucose sensor system is provided,the sensor system comprising a mounting unit adapted for mounting on askin of a host; a sensor configured to measure an analyte concentrationin the host; sensor electronics operably connected to the sensor,wherein the sensor is configured to provide data representative of ananalyte concentration in the host; a receiver remote from the mountingunit and configured to receive sensor data from the electronics unitrepresentative of a measured analyte concentration; and an informationtag configured to provide sensor information selected from the groupconsisting of manufacturing information, calibration information,identification information, expiration information, sensor durationinformation, archived data, license code information, and combinationsthereof.

In an embodiment of the twelfth aspect, the receiver is configured toread sensor information from the information tag.

In an embodiment of the twelfth aspect, the electronics unit isconfigured to releasably mate with the mounting unit, and wherein theelectronics unit is operably connected to the sensor when theelectronics unit is mated to the mounting unit.

In a thirteenth aspect, a device configured for placement on a skinsurface of a host is provided, the device comprising a sensor configuredfor transcutaneous insertion into a host and operatively connected tosensor electronics for processing data obtained from the sensor; and ahousing adapted for placement on a skin surface of the host and coupledto the sensor electronics, wherein at least one of the housing and thesensor electronics comprises a user interface configured to communicateinformation responsive to processed sensor data.

In an embodiment of the thirteenth aspect, the user interface comprisesa screen configured to display at least one numerical value.

In an embodiment of the thirteenth aspect, the user interface comprisesa screen configured to display trend information.

In an embodiment of the thirteenth aspect, the user interface comprisesa screen configured to display graphical information.

In an embodiment of the thirteenth aspect, the user interface isconfigured to communicate information audibly.

In an embodiment of the thirteenth aspect, the user interface isconfigured to communicate information tactilely.

In an embodiment of the thirteenth aspect, the user interface isconfigured to provide information to the host in response to activationof a button.

In an embodiment of the thirteenth aspect, the sensor electronics areconfigured to alert the host when the sensor data is outside apredetermined boundary.

In an embodiment of the thirteenth aspect, the sensor electronics areconfigured to filter the sensor data.

In an embodiment of the thirteenth aspect, the sensor electronics areconfigured to calibrate the sensor data.

In an embodiment of the thirteenth aspect, the device further comprisesa receiver, wherein the receiver is configured to communicate with thesensor electronics.

In an embodiment of the thirteenth aspect, the receiver is configured torequest information from the sensor electronics.

In an embodiment of the thirteenth aspect, the sensor electronics areconfigured to transmit sensor data responsive to a request by thereceiver.

In an embodiment of the thirteenth aspect, the receiver and the sensorelectronics are operatively connected by at least one connectionselected from the group consisting of a cable, a radio frequencyconnection, an optical connection, an inductive coupling connection, aninfrared connection, and a microwave connection.

In an embodiment of the thirteenth aspect, the sensor electronics arereleasably attachable to the housing.

In a fourteenth aspect, a transcutaneous glucose sensing device isprovided, the device comprising a glucose sensor configured fortranscutaneous insertion through a skin of a host; and an on-skinhousing coupled to the sensor, wherein the on-skin housing is adhered tothe skin, and wherein the on-skin housing comprises sensor electronicsconfigured to process sensor data and to provide sensor data to the hostvia a user interface.

In an embodiment of the fourteenth aspect, the user interface isconfigured to provide sensor data by at least method selected from thegroup consisting of visually, audibly, and tactilely.

In an embodiment of the fourteenth aspect, the user interface is housedon or in the on-skin housing.

In an embodiment of the fourteenth aspect, the user interface isoperatively connected to the on-skin housing via at least one wire.

In an embodiment of the fourteenth aspect, the user interface isconfigured to be worn on the host at a location remote from the on-skinhousing.

In an embodiment of the fourteenth aspect, the user interface isconfigured to be worn on clothing of the host, and wherein the on-skinhousing in configured to be worn on the skin of the host.

In an embodiment of the fourteenth aspect, the user interface isdirectly wired to the on-skin housing.

In an embodiment of the fourteenth aspect, the sensor electronics arereleasably attachable to the on-skin housing.

In a fifteenth aspect, a transcutaneous glucose sensor system isprovided, the system comprising a glucose sensor configured fortranscutaneous insertion through skin of a host; an on-skin devicecoupled to the sensor and comprising electronics configured to processdata obtained from the sensor; and a receiver remote from the on-skindevice configured to request information from the on-skin device.

In an embodiment of the fifteenth aspect, the on-skin device isconfigured to provide sensor information indicative of a glucose valueof the host by at least one method selected from the group consisting ofvisual, audible, and tactile.

In an embodiment of the fifteenth aspect, the on-skin device isconfigured to provide filtered sensor data by at least one methodselected from the group consisting of visual, audible, and tactile.

In an embodiment of the fifteenth aspect, the on-skin device isconfigured to provide calibrated sensor data by at least one methodselected from the group consisting of visual, audible, and tactile.

In a sixteenth aspect, a system configured to control use of a medicaldevice is provided, the system comprising a reusable device and at leastone single-use device, the single-use device being associated with thereusable device; and a hardware key comprising a memory with informationstored therein, wherein the hardware key is configured to operativelyconnect to the reusable device and to transmit at least a portion of theinformation to the reusable device.

In an embodiment of the sixteenth aspect, the hardware key is a dongle.

In an embodiment of the sixteenth aspect, the hardware key comprises alicense comprising information selected from the group consisting ofmanufacturing information, calibration information, identificationinformation, expiration information, duration information, insertioninformation, and combinations thereof.

In an embodiment of the sixteenth aspect, at least some of theinformation is encrypted in the memory of the hardware key.

In an embodiment of the sixteenth aspect, the reusable device isconfigured to authenticate the hardware key upon operative connectionthereto.

In an embodiment of the sixteenth aspect, the reusable device isconfigured to read information from the hardware key.

In an embodiment of the sixteenth aspect, the reusable device isconfigured to mark or erase at least a portion of the information in thememory of the hardware key to ensure the hardware key is used only apredetermined number of times.

In an embodiment of the sixteenth aspect, the reusable device isconfigured to mark or erase at least a portion of the information in thememory of the hardware key to ensure the hardware key is used only once.

In an embodiment of the sixteenth aspect, the reusable device comprisesa receiver and the single-use device comprises at least one analytesensor, and the receiver is configured to receive, process, or displaydata from the analyte sensor.

In an embodiment of the sixteenth aspect, the receiver is configured tocontrol an amount of time over which data is obtained from the analytesensor responsive to receipt of information from the hardware key.

In an embodiment of the sixteenth aspect, the hardware key is configuredto physically connect to a port on the reusable device.

In an embodiment of the sixteenth aspect, the medical device comprisesan implantable glucose sensor system, the reusable device comprises areceiver, and the single-use device comprises a transcutaneous glucosesensor.

In an embodiment of the sixteenth aspect, the hardware key is packagedwith the one or more transcutaneous glucose sensors, and the hardwarekey is configured to limit the duration of or number of insertions ofthe one or more transcutaneous glucose sensors.

In a seventeenth aspect, a method of limiting use of a medical device isprovided, the method comprising providing a hardware key associated witha single-use device, wherein the hardware key is configured to controlan amount of time over which data is obtained from the single-usedevice; and providing a reusable device comprising a port for connectingthe hardware key thereto.

In an embodiment of the seventeenth aspect, the method further comprisesconnecting the hardware key to the reusable device.

In an embodiment of the seventeenth aspect, the method further comprisestransmitting encrypted information from the hardware key to the reusabledevice.

In an embodiment of the seventeenth aspect, the transmitting stepcomprises transmitting at least one of manufacturing information,calibration information, identification information, expirationinformation, duration information, and insertion information.

In an embodiment of the seventeenth aspect, the method further comprisesauthenticating the hardware key upon operative connection to thereusable device.

In an embodiment of the seventeenth aspect, the method further comprisesreading information from the hardware key upon operative connection tothe reusable device.

In an embodiment of the seventeenth aspect, the method further comprisesmarking or erasing at least a portion of the information from thehardware key after the step of reading information from the hardware keyto ensure the hardware key is used only a predetermined number of times.

In an embodiment of the seventeenth aspect, the marking or erasing stepcomprises marking or erasing at least a portion of the information fromthe hardware key to ensure the hardware key is used only one time.

In an embodiment of the seventeenth aspect, the reusable devicecomprises a receiver, and the receiver receives, processes, or displaysdata from the single-use device.

In an embodiment of the seventeenth aspect, the medical device comprisesan implantable glucose sensor system, the reusable device comprises areceiver, and the single-use device comprises a transcutaneous glucosesensor.

In an embodiment of the seventeenth aspect, the hardware key isconfigured to limit a duration of insertion or a number of insertions ofthe transcutaneous glucose sensor.

In an eighteenth aspect, a sensor system configured to measure ananalyte concentration in a host is provided, the system comprising atleast one sensor configured to be implanted in a host and configured tomeasure an analyte concentration in a tissue of the host; a receiveroperatively connectable to the sensor and configured to provide analytedata representative of an analyte concentration in the host; and ahardware key configured to connect to the receiver, wherein the hardwarekey comprises information selected from the group consisting ofmanufacturing information, calibration information, identificationinformation, expiration information, duration information, insertioninformation, and combinations thereof.

In an embodiment of the eighteenth aspect, the method further comprisespackaging configured to contain the sensor and the hardware key.

In an embodiment of the eighteenth aspect, the hardware key isprogrammed with a license code.

In an embodiment of the eighteenth aspect, the license code comprisesinformation configured to control a duration of insertion or a number ofinsertions of the sensor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a transcutaneous analyte sensor system,including an applicator, a mounting unit, and an electronics unit.

FIG. 2 is a perspective view of a mounting unit, including theelectronics unit in its functional position.

FIG. 3 is an exploded perspective view of a mounting unit, showing itsindividual components.

FIG. 4A is an exploded perspective view of a contact subassembly,showing its individual components.

FIG. 4B is a perspective view of an alternative contact configuration.

FIG. 4C is a perspective view of another alternative contactconfiguration.

FIGS. 4D to 4H are schematic cross-sectional views of a portion of thecontact subassembly; namely, a variety of embodiments illustratingalternative sealing member configurations.

FIG. 5A is an expanded cutaway view of a proximal portion of a sensor.

FIG. 5B is an expanded cutaway view of a distal portion of a sensor.

FIG. 5C is a cross-sectional view through the sensor of FIG. 5B on lineC-C, showing an exposed electroactive surface of a working electrodesurrounded by a membrane system.

FIG. 6 is an exploded side view of an applicator, showing the componentsthat facilitate sensor insertion and subsequent needle retraction.

FIGS. 7A to 7D are schematic side cross-sectional views that illustrateapplicator components and their cooperating relationships.

FIG. 8A is a perspective view of an applicator and mounting unit in oneembodiment including a safety latch mechanism.

FIG. 8B is a side view of an applicator matingly engaged to a mountingunit in one embodiment, prior to sensor insertion.

FIG. 8C is a side view of a mounting unit and applicator depicted in theembodiment of FIG. 8B, after the plunger subassembly has been pushed,extending the needle and sensor from the mounting unit.

FIG. 8D is a side view of a mounting unit and applicator depicted in theembodiment of FIG. 8B, after the guide tube subassembly has beenretracted, retracting the needle back into the applicator.

FIG. 8E is a perspective view of an applicator, in an alternativeembodiment, matingly engaged to the mounting unit after to sensorinsertion.

FIG. 8F is a perspective view of the mounting unit and applicator, asdepicted in the alternative embodiment of FIG. 8E, matingly engagedwhile the electronics unit is slidingly inserted into the mounting unit.

FIG. 8G is a perspective view of the electronics unit, as depicted inthe alternative embodiment of FIG. 8E, matingly engaged to the mountingunit after the applicator has been released.

FIGS. 8H and 8I are comparative top views of the sensor system shown inthe alternative embodiment illustrated in FIGS. 8E to 8G as compared tothe embodiments illustrated in FIGS. 8B to 8D.

FIGS. 9A to 9C are side views of an applicator and mounting unit,showing stages of sensor insertion.

FIGS. 10A and 10B are perspective and side cross-sectional views,respectively, of a sensor system showing the mounting unit immediatelyfollowing sensor insertion and release of the applicator from themounting unit.

FIGS. 11A and 11B are perspective and side cross-sectional views,respectively, of a sensor system showing the mounting unit afterpivoting the contact subassembly to its functional position.

FIGS. 12A to 12C are perspective and side views, respectively, of thesensor system showing the sensor, mounting unit, and electronics unit intheir functional positions.

FIG. 13 is an exploded perspective view of one exemplary embodiment of acontinuous glucose sensor

FIG. 14A is a block diagram that illustrates electronics associated witha sensor system.

FIG. 14B is a perspective view of an alternative embodiment, wherein theelectronics unit and/or mounting unit, hereinafter referred to as the“on-skin device,” is configured to communicate sensor informationdirectly to the user (e.g., host).

FIG. 15 is a perspective view of a sensor system wirelesslycommunicating with a receiver.

FIG. 16A illustrates a first embodiment wherein the receiver shows anumeric representation of the estimated analyte value on its userinterface, which is described in more detail elsewhere herein.

FIG. 16B illustrates a second embodiment wherein the receiver shows anestimated glucose value and one hour of historical trend data on itsuser interface, which is described in more detail elsewhere herein.

FIG. 16C illustrates a third embodiment wherein the receiver shows anestimated glucose value and three hours of historical trend data on itsuser interface, which is described in more detail elsewhere herein.

FIG. 16D illustrates a fourth embodiment wherein the receiver shows anestimated glucose value and nine hours of historical trend data on itsuser interface, which is described in more detail elsewhere herein.

FIG. 17A is a block diagram that illustrates a configuration of amedical device including a continuous analyte sensor, a receiver, and anexternal device.

FIGS. 17B to 17D are illustrations of receiver liquid crystal displaysshowing embodiments of screen displays.

FIG. 18A is a flow chart that illustrates the initial calibration anddata output of sensor data.

FIG. 18B is a graph that illustrates an example of using priorinformation for slope and baseline. FIGS. 18C-18G disclose integratedreceiver housing 1892 and stylus 1998.

FIG. 19A is a flow chart that illustrates evaluation of reference and/orsensor data for statistical, clinical, and/or physiologicalacceptability.

FIG. 19B is a graph of two data pairs on a Clarke Error Grid toillustrate the evaluation of clinical acceptability in one exemplaryembodiment.

FIG. 20 is a flow chart that illustrates evaluation of calibrated sensordata for aberrant values.

FIG. 21 is a flow chart that illustrates self-diagnostics of sensordata.

FIGS. 22A and 22B are graphical representations of glucose sensor datain a human obtained over approximately three days.

FIG. 23A is a graphical representation of glucose sensor data in a humanobtained over approximately seven days.

FIG. 23B is a flow chart that illustrates a method for distributing andcontrolling use of sensor systems with disposable and single-use parts.

FIG. 24A is a bar graph that illustrates the ability of sensors toresist uric acid pre- and post-electron beam exposure in one in vitroexperiment.

FIG. 24B is a bar graph that illustrates the ability of sensors toresist ascorbic acid pre- and post-electron beam exposure in one invitro experiment.

FIG. 24C is a bar graph that illustrates the ability of sensors toresist acetaminophen pre- and post-electron beam exposure in one invitro experiment.

FIG. 25A is a graphical representation that illustrates theacetaminophen blocking ability of a glucose sensor including a celluloseacetate interference domain that has been treated using electron beamradiation and tested in vivo.

FIG. 25B is a graphical representation that illustrates theacetaminophen blocking ability of a glucose sensor including a celluloseacetate/Nafion® interference domain that has been treated using electronbeam radiation and tested in vivo.

FIG. 25C is a graphical representation that illustrates the lack ofacetaminophen blocking ability of a control glucose sensor without aninterference domain and tested in vivo.

FIG. 26A is a bar graph that represents the break-in time of the testsensors vs. the control sensors.

FIG. 26B is a graph that represents the response of glucose sensors to avariety of interferents.

FIG. 26C is a graph that represents an “equivalent glucose signal”caused by the interferents tested.

FIG. 27 is a photomicrograph obtained by Scanning Electron Microscopy(SEM) at 350× magnification of a sensor including a vapor depositedresistance domain on an outer surface.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate some exemplaryembodiments of the disclosed invention in detail. Those of skill in theart will recognize that there are numerous variations and modificationsof this invention that are encompassed by its scope. Accordingly, thedescription of a certain exemplary embodiment should not be deemed tolimit the scope of the present invention.

Definitions

In order to facilitate an understanding of the preferred embodiments, anumber of terms are defined below.

The term “analyte” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a substance or chemical constituent in abiological fluid (for example, blood, interstitial fluid, cerebralspinal fluid, lymph fluid or urine) that can be analyzed. Analytes caninclude naturally occurring substances, artificial substances,metabolites, and/or reaction products. In some embodiments, the analytefor measurement by the sensing regions, devices, and methods is glucose.However, other analytes are contemplated as well, including but notlimited to acarboxyprothrombin; acylcarnitine; adenine phosphoribosyltransferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acidprofiles (arginine (Krebs cycle), histidine/urocanic acid, homocysteine,phenylalanine/tyrosine, tryptophan); andrenostenedione; antipyrine;arabinitol enantiomers; arginase; benzoylecgonine (cocaine);biotinidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4;ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol;cholinesterase; conjugated 1-β hydroxy-cholic acid; cortisol; creatinekinase; creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine;de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylatorpolymorphism, alcohol dehydrogenase, alpha 1-antitrypsin, cysticfibrosis, Duchenne/Becker muscular dystrophy, glucose-6-phosphatedehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D,hemoglobin E, hemoglobin F, D-Punjab, beta-thalassemia, hepatitis Bvirus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD,RNA, PKU, Plasmodium vivax, sexual differentiation, 21-deoxycortisol);desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanusantitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D;fatty acids/acylglycines; free β-human chorionic gonadotropin; freeerythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphatedehydrogenase; glutathione; glutathione perioxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I;17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, β);lysozyme; mefloquine; netilmicin; phenobarbitone; phenyloin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody,arbovirus, Aujeszky's disease virus, dengue virus, Dracunculusmedinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus,Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmaniadonovani, leptospira, measles/mumps/rubella, Mycobacterium leprae,Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenzavirus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa,respiratory syncytial virus, rickettsia (scrub typhus), Schistosomamansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosomacruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellowfever virus); specific antigens (hepatitis B virus, HIV-1);succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine(T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins, and hormones naturally occurring in blood or interstitialfluids can also constitute analytes in certain embodiments. The analytecan be naturally present in the biological fluid, for example, ametabolic product, a hormone, an antigen, an antibody, and the like.Alternatively, the analyte can be introduced into the body, for example,a contrast agent for imaging, a radioisotope, a chemical agent, afluorocarbon-based synthetic blood, or a drug or pharmaceuticalcomposition, including but not limited to insulin; ethanol; cannabis(marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide,amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine(crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin,Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine);depressants (barbituates, methaqualone, tranquilizers such as Valium,Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens(phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics(heroin, codeine, morphine, opium, meperidine, Percocet, Percodan,Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogsof fentanyl, meperidine, amphetamines, methamphetamines, andphencyclidine, for example, Ecstasy); anabolic steroids; and nicotine.The metabolic products of drugs and pharmaceutical compositions are alsocontemplated analytes. Analytes such as neurochemicals and otherchemicals generated within the body can also be analyzed, such as, forexample, ascorbic acid, uric acid, dopamine, noradrenaline,3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC),homovanillic acid (HVA), 5-hydroxytryptamine (5HT), histamine, AdvancedGlycation End Products (AGEs) and 5-hydroxyindoleacetic acid (FHIAA).

The term “host” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to mammals, particularly humans.

The term “exit-site” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the area where a medical device (forexample, a sensor and/or needle) exits from the host's body.

The term “continuous (or continual) analyte sensing” as used herein is abroad term, and is to be given its ordinary and customary meaning to aperson of ordinary skill in the art (and is not to be limited to aspecial or customized meaning), and refers without limitation to theperiod in which monitoring of analyte concentration is continuously,continually, and or intermittently (regularly or irregularly) performed,for example, about every 5 to 10 minutes.

The term “electrochemically reactive surface” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to the surface of anelectrode where an electrochemical reaction takes place. For example, aworking electrode measures hydrogen peroxide produced by theenzyme-catalyzed reaction of the analyte detected, which reacts tocreate an electric current. Glucose analyte can be detected utilizingglucose oxidase, which produces H₂O₂ as a byproduct. H₂O₂ reacts withthe surface of the working electrode, producing two protons (2H⁺), twoelectrons (2e⁻) and one molecule of oxygen (O₂), which produces theelectronic current being detected.

The term “electronic connection” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to any electronic connectionknown to those in the art that can be utilized to interface the sensingregion electrodes with the electronic circuitry of a device, such asmechanical (for example, pin and socket) or soldered electronicconnections.

The term “sensing region” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the region of a monitoringdevice responsible for the detection of a particular analyte. Thesensing region generally comprises a non-conductive body, a workingelectrode (anode), a reference electrode (optional), and/or a counterelectrode (cathode) passing through and secured within the body formingelectrochemically reactive surfaces on the body and an electronicconnective means at another location on the body, and a multi-domainmembrane affixed to the body and covering the electrochemically reactivesurface.

The term “high oxygen solubility domain” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a domain composedof a material that has higher oxygen solubility than aqueous media suchthat it concentrates oxygen from the biological fluid surrounding themembrane system. The domain can act as an oxygen reservoir during timesof minimal oxygen need and has the capacity to provide, on demand, ahigher oxygen gradient to facilitate oxygen transport across themembrane. Thus, the ability of the high oxygen solubility domain tosupply a higher flux of oxygen to critical domains when needed canimprove overall sensor function.

The term “domain” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a region of the membrane system that can bea layer, a uniform or non-uniform gradient (for example, an anisotropicregion of a membrane), or a portion of a membrane.

The term “distal to” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the spatial relationship between variouselements in comparison to a particular point of reference. In general,the term indicates an element is located relatively far from thereference point than another element.

The term “proximal to” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the spatial relationshipbetween various elements in comparison to a particular point ofreference. In general, the term indicates an element is locatedrelatively near to the reference point than another element.

The term “in vivo portion” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the portion of the device(for example, a sensor) adapted for insertion into and/or existencewithin a living body of a host.

The term “ex vivo portion” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the portion of the device(for example, a sensor) adapted to remain and/or exist outside of aliving body of a host.

The terms “raw data stream”, “raw data signal”, and “data stream” asused herein are broad terms, and are to be given their ordinary andcustomary meaning to a person of ordinary skill in the art (and are notto be limited to a special or customized meaning), and refer withoutlimitation to an analog or digital signal from the analyte sensordirectly related to the measured analyte. For example, the raw datastream is digital data in “counts” converted by an A/D converter from ananalog signal (for example, voltage or amps) representative of ananalyte concentration. The terms broadly encompass a plurality of timespaced data points from a substantially continuous analyte sensor, eachof which comprises individual measurements taken at time intervalsranging from fractions of a second up to, for example, 1, 2, or 5minutes or longer.

The term “count” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a unit of measurement of a digital signal.For example, a raw data stream or raw data signal measured in counts isdirectly related to a voltage (for example, converted by an A/Dconverter), which is directly related to current from the workingelectrode.

The term “physiologically feasible” as used herein is a broad term, andis to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to one or morephysiological parameters obtained from continuous studies of glucosedata in humans and/or animals. For example, a maximal sustained rate ofchange of glucose in humans of about 4 mg/dL/min to about 6 mg/dL/minand a maximum acceleration of the rate of change of about 0.1mg/dL/min/min to about 0.2 mg/dL/min/min are deemed physiologicallyfeasible limits. Values outside of these limits are considerednon-physiological and are likely a result of, e.g., signal error.

The term “ischemia” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to local and temporary deficiency of bloodsupply due to obstruction of circulation to a part (for example, asensor). Ischemia can be caused, for example, by mechanical obstruction(for example, arterial narrowing or disruption) of the blood supply.

The term “matched data pairs” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to reference data (for example,one or more reference analyte data points) matched with substantiallytime corresponding sensor data (for example, one or more sensor datapoints).

The term “Clarke Error Grid” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to an error grid analysis, forexample, an error grid analysis used to evaluate the clinicalsignificance of the difference between a reference glucose value and asensor generated glucose value, taking into account 1) the value of thereference glucose measurement, 2) the value of the sensor glucosemeasurement, 3) the relative difference between the two values, and 4)the clinical significance of this difference. See Clarke et al.,“Evaluating Clinical Accuracy of Systems for Self-Monitoring of BloodGlucose” Diabetes Care, Volume 10, Number 5, September-October 1987.

The term “Consensus Error Grid” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to an error grid analysis thatassigns a specific level of clinical risk to any possible error betweentwo time corresponding measurements, e.g., glucose measurements. TheConsensus Error Grid is divided into zones signifying the degree of riskposed by the deviation. See Parkes et al., “A New Consensus Error Gridto Evaluate the Clinical Significance of Inaccuracies in the Measurementof Blood Glucose” Diabetes Care, Volume 23, Number 8, August 2000.

The term “clinical acceptability” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to determination of the risk ofan inaccuracy to a patient. Clinical acceptability considers a deviationbetween time corresponding analyte measurements (for example, data froma glucose sensor and data from a reference glucose monitor) and the risk(for example, to the decision making of a person with diabetes)associated with that deviation based on the analyte value indicated bythe sensor and/or reference data. An example of clinical acceptabilitycan be 85% of a given set of measured analyte values within the “A” and“B” region of a standard Clarke Error Grid when the sensor measurementsare compared to a standard reference measurement.

The terms “sensor” and “sensor system” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to the component orregion of a device by which an analyte can be quantified.

The term “needle” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a slender hollow instrument for introducingmaterial into or removing material from the body.

The terms “operatively connected,” “operatively linked,” “operablyconnected,” and “operably linked” as used herein are broad terms, andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to one or morecomponents linked to one or more other components. The terms can referto a mechanical connection, an electrical connection, or a connectionthat allows transmission of signals between the components. For example,one or more electrodes can be used to detect the amount of analyte in asample and to convert that information into a signal; the signal canthen be transmitted to a circuit. In such an example, the electrode is“operably linked” to the electronic circuitry.

The term “baseline” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the component of an analyte sensor signalthat is not related to the analyte concentration. In one example of aglucose sensor, the baseline is composed substantially of signalcontribution due to factors other than glucose (for example, interferingspecies, non-reaction-related hydrogen peroxide, or other electroactivespecies with an oxidation potential that overlaps with hydrogenperoxide). In some embodiments wherein a calibration is defined bysolving for the equation y=m×+b, the value of b represents the baselineof the signal.

The terms “sensitivity” and “slope” as used herein are broad terms, andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to an amount ofelectrical current produced by a predetermined amount (unit) of themeasured analyte. For example, in one preferred embodiment, a sensor hasa sensitivity (or slope) of about 3.5 to about 7.5 picoAmps of currentfor every 1 mg/dL of glucose analyte.

The term “membrane system” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a permeable or semi-permeablemembrane that can be comprised of two or more domains and is typicallyconstructed of materials of one or more microns in thickness, which ispermeable to oxygen and is optionally permeable to, e.g., glucose oranother analyte. In one example, the membrane system comprises animmobilized glucose oxidase enzyme, which enables a reaction to occurbetween glucose and oxygen whereby a concentration of glucose can bemeasured.

The terms “processor module” and “microprocessor” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to acomputer system, state machine, processor, or the like designed toperform arithmetic or logic operations using logic circuitry thatresponds to and processes the basic instructions that drive a computer.

The terms “smoothing” and “filtering” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to modification of aset of data to make it smoother and more continuous or to remove ordiminish outlying points, for example, by performing a moving average ofthe raw data stream.

The term “algorithm” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a computational process (for example,programs) involved in transforming information from one state toanother, for example, by using computer processing.

The term “regression” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to finding a line for which a set of data hasa minimal measurement (for example, deviation) from that line.Regression can be linear, non-linear, first order, second order, or thelike. One example of regression is least squares regression.

The term “calibration” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the process of determiningthe relationship between the sensor data and the corresponding referencedata, which can be used to convert sensor data into meaningful valuessubstantially equivalent to the reference data. In some embodiments,namely, in continuous analyte sensors, calibration can be updated orrecalibrated over time as changes in the relationship between the sensordata and reference data occur, for example, due to changes insensitivity, baseline, transport, metabolism, or the like.

The terms “interferents” and “interfering species” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to effectsand/or species that interfere with the measurement of an analyte ofinterest in a sensor to produce a signal that does not accuratelyrepresent the analyte concentration. In one example of anelectrochemical sensor, interfering species are compounds with anoxidation potential that overlap that of the analyte to be measured,thereby producing a false positive signal.

The terms “chloridization” and “chloridizing” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation totreatment or preparation with chloride. The term “chloride” as usedherein, is a broad term and is used in its ordinary sense, including,without limitation, to refer to Cl⁻ ions, sources of Cl⁻ ions, and saltsof hydrochloric acid. Chloridization and chloridizing methods include,but are not limited to, chemical and electrochemical methods.

The term “R-value” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to one conventional way of summarizing thecorrelation of data; that is, a statement of what residual (e.g., rootmean square deviations) are to be expected if the data are fitted to astraight line by the a regression.

The terms “data association” and “data association function” as usedherein are broad terms, and are to be given their ordinary and customarymeaning to a person of ordinary skill in the art (and are not to belimited to a special or customized meaning), and refer withoutlimitation to a statistical analysis of data and particularly itscorrelation to, or deviation from, from a particular curve. A dataassociation function is used to show data association. For example, thedata that forms that calibration set as described herein can be analyzedmathematically to determine its correlation to, or deviation from, acurve (e.g., line or set of lines) that defines the conversion function;this correlation or deviation is the data association. A dataassociation function is used to determine data association. Examples ofdata association functions include, but are not limited to, linearregression, non-linear mapping/regression, rank (e.g., non-parametric)correlation, least mean square fit, mean absolute deviation (MAD), meanabsolute relative difference. In one such example, the correlationcoefficient of linear regression is indicative of the amount of dataassociation of the calibration set that forms the conversion function,and thus the quality of the calibration.

The term “quality of calibration” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the statistical associationof matched data pairs in the calibration set used to create theconversion function. For example, an R-value can be calculated for acalibration set to determine its statistical data association, whereinan R-value greater than 0.79 determines a statistically acceptablecalibration quality, while an R-value less than 0.79 determinesstatistically unacceptable calibration quality.

The term “congruence” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the quality or state of agreeing,coinciding, or being concordant. In one example, congruence can bedetermined using rank correlation.

The term “concordant” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to being in agreement or harmony, and/or freefrom discord.

The phrase “continuous glucose sensing” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to the period inwhich monitoring of plasma glucose concentration is continuously orcontinually performed, for example, at time intervals ranging fromfractions of a second up to, for example, 1, 2, or 5 minutes, or longer.

The term “single point glucose monitor” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a device that canbe used to measure a glucose concentration within a host at a singlepoint in time, for example, some embodiments utilize a small volume invitro glucose monitor that includes an enzyme membrane such as describedwith reference to U.S. Pat. No. 4,994,167 and U.S. Pat. No. 4,757,022.It should be understood that single point glucose monitors can measuremultiple samples (for example, blood, or interstitial fluid); howeveronly one sample is measured at a time and typically requires some userinitiation and/or interaction.

The term “biological sample” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to sample of a host body, forexample blood, interstitial fluid, spinal fluid, saliva, urine, tears,sweat, or the like.

The terms “substantial” and “substantially” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to asufficient amount that provides a desired function. For example, theinterference domain of the preferred embodiments is configured to resista sufficient amount of interfering species such that tracking of glucoselevels can be achieved, which may include an amount greater than 50percent, an amount greater than 60 percent, an amount greater than 70percent, an amount greater than 80 percent, and an amount greater than90 percent of interfering species.

The terms “cellulosic derivatives” and “cellulosic polymers” as usedherein are broad terms, and are to be given their ordinary and customarymeaning to a person of ordinary skill in the art (and are not to belimited to a special or customized meaning), and refer withoutlimitation to derivatives of cellulose formed by reaction withcarboxylic acid anhydrides. Examples of cellulosic derivatives includecellulose acetate, 2-hydroxyethyl cellulose, cellulose acetatephthalate, cellulose acetate propionate, cellulose acetate butyrate,cellulose acetate trimellitate, and the like.

The term “cellulose acetate” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to any of several compoundsobtained by treating cellulose with acetic anhydride.

The term “cellulose acetate butyrate” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to any of severalcompounds obtained by treating cellulose with acetic anhydride andbutyric anhydride.

The term “Nafion®” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to DuPont's trademark of a sulfonatedtetrafluorethylene polymer modified from Teflon® developed in the late1960s. In general, Nafion® is a perfluorinated polymer that containssmall proportions of sulfonic or carboxylic ionic functional groups.

The terms “crosslink” and “crosslinking” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to joining (adjacentchains of a polymer or protein) by creating covalent bonds. Crosslinkingcan be accomplished by techniques such as thermal reaction, chemicalreaction or by providing ionizing radiation (for example, electron beamradiation, UV radiation, or gamma radiation). In preferred embodiments,crosslinking utilizes a technique that forms free radicals, for example,electron beam exposure.

The term “ionizing radiation” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to radiation consisting ofparticles, X-ray beams, electron beams, UV beams, or gamma ray beams,which produce ions in the medium through which it passes.

The term “casting” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a process where a fluid material is appliedto a surface or surfaces and allowed to cure or dry. The term is broadenough to encompass a variety of coating techniques, for example, usinga draw-down machine (i.e., drawing-down), dip coating, spray coating,spin coating, or the like.

The term “dip coating” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to coating which involvesdipping an object or material into a liquid coating substance.

The term “spray coating” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to coating which involvesspraying a liquid coating substance onto an object or material.

The term “spin coating” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a coating process in which athin film is created by dropping a raw material solution onto asubstrate while it is rotating.

The terms “solvent” and “solvent systems” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation tosubstances (e.g., liquids) capable of dissolving or dispersing one ormore other substances. Solvents and solvent systems can includecompounds and/or solutions that include components in addition to thesolvent itself.

The term “baseline” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the component of an analyte sensor signalthat is not related to the analyte concentration. In one example of aglucose sensor, the baseline is composed substantially of signalcontribution due to factors other than glucose (for example, interferingspecies, non-reaction-related hydrogen peroxide, or other electroactivespecies with an oxidation potential that overlaps with hydrogenperoxide). In some embodiments wherein a calibration is defined bysolving for the equation y=m×+b, the value of b represents the baselineof the signal.

The terms “sensitivity” and “slope” as used herein are broad terms, andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to an amount ofelectrical current produced by a predetermined amount (unit) of themeasured analyte. For example, in one preferred embodiment, a sensor hasa sensitivity (or slope) of about 3.5 to about 7.5 picoAmps of currentfor every 1 mg/dL of glucose analyte.

The terms “baseline and/or sensitivity shift,” “baseline and/orsensitivity drift,” “shift,” and “drift” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to a change in thebaseline and/or sensitivity of the sensor signal over time. While theterm “shift” generally refers to a substantially distinct change over arelatively short time period, and the term “drift” generally refers to asubstantially gradual change over a relatively longer time period, theterms can be used interchangeably and can also be generally referred toas “change” in baseline and/or sensitivity.

The terms “sealant” and “lubricant” as used herein are broad terms, andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to a material with alow surface tension that repels and/or blocks moisture, for example,oil, grease, or gel. Sealants or lubricants can be used to fill gapsand/or to repel or block water. One exemplary sealant is petroleumjelly.

Sensor System

The preferred embodiments relate to the use of an analyte sensor thatmeasures a concentration of analyte of interest or a substanceindicative of the concentration or presence of the analyte. In someembodiments, the sensor is a continuous device, for example asubcutaneous, transdermal (e.g., transcutaneous), or intravasculardevice. In some embodiments, the device can analyze a plurality ofintermittent blood samples. The analyte sensor can use any method ofanalyte-sensing, including enzymatic, chemical, physical,electrochemical, spectrophotometric, polarimetric, calorimetric,radiometric, or the like.

The analyte sensor uses any method, including invasive, minimallyinvasive, and non-invasive sensing techniques, to provide an outputsignal indicative of the concentration of the analyte of interest. Theoutput signal is typically a raw signal that is used to provide a usefulvalue of the analyte of interest to a user, such as a patient orphysician, who can be using the device. Accordingly, appropriatesmoothing, calibration, and evaluation methods can be applied to the rawsignal and/or system as a whole to provide relevant and acceptableestimated analyte data to the user.

The methods and devices of preferred embodiments can be employed in acontinuous glucose sensor that measures a concentration of glucose or asubstance indicative of a concentration or a presence of glucose.However, certain methods and devices of preferred embodiments are alsosuitable for use in connection with non-continuous (e.g., single pointmeasurement or finger stick) monitors, such as the OneTouch® systemmanufactured by LifeScan, Inc., or monitors as disclosed in U.S. Pat.Nos. 5,418,142; 5,515,170; 5,526,120; 5,922,530; 5,968,836; and6,335,203. In some embodiments, the glucose sensor is an invasive,minimally-invasive, or non-invasive device, for example a subcutaneous,transdermal, or intravascular device. In some embodiments, the devicecan analyze a plurality of intermittent biological samples, such asblood, interstitial fluid, or the like. The glucose sensor can use anymethod of glucose-measurement, including calorimetric, enzymatic,chemical, physical, electrochemical, spectrophotometric, polarimetric,calorimetric, radiometric, or the like. In alternative embodiments, thesensor can be any sensor capable of determining the level of an analytein the body, for example oxygen, lactase, hormones, cholesterol,medicaments, viruses, or the like.

The glucose sensor uses any method to provide an output signalindicative of the concentration of the glucose. The output signal istypically a raw data stream that is used to provide a value indicativeof the measured glucose concentration to a patient or doctor, forexample.

One exemplary embodiment described in detail below utilizes animplantable glucose sensor. Another exemplary embodiment described indetail below utilizes a transcutaneous glucose sensor.

In one alternative embodiment, the continuous glucose sensor comprises atranscutaneous sensor such as described in U.S. Pat. No. 6,565,509 toSay et al. In another alternative embodiment, the continuous glucosesensor comprises a subcutaneous sensor such as described with referenceto U.S. Pat. No. 6,579,690 to Bonnecaze et al. or U.S. Pat. No.6,484,046 to Say et al. In another alternative embodiment, thecontinuous glucose sensor comprises a refillable subcutaneous sensorsuch as described with reference to U.S. Pat. No. 6,512,939 to Colvin etal. In another alternative embodiment, the continuous glucose sensorcomprises an intravascular sensor such as described with reference toU.S. Pat. No. 6,477,395 to Schulman et al. In another alternativeembodiment, the continuous glucose sensor comprises an intravascularsensor such as described with reference to U.S. Pat. No. 6,424,847 toMastrototaro et al. All of the above patents are incorporated in theirentirety herein by reference.

Although a few exemplary embodiments of continuous glucose sensors areillustrated and described herein, it should be understood that thedisclosed embodiments are applicable to any device capable of singleanalyte, substantially continual or substantially continuous measurementof a concentration of analyte of interest and providing an output signalthat represents the concentration of that analyte.

In a first exemplary embodiment, a transcutaneous analyte sensor systemis provided that includes an applicator for inserting the transdermalanalyte sensor under a host's skin. The sensor system includes a sensorfor sensing the analyte, wherein the sensor is associated with amounting unit adapted for mounting on the skin of the host. The mountingunit houses the electronics unit associated with the sensor and isadapted for fastening to the host's skin. In certain embodiments, thesystem further includes a receiver for receiving and/or processingsensor data.

FIG. 1 is a perspective view of a transcutaneous analyte sensor system10. In the preferred embodiment of a system as depicted in FIG. 1, thesensor includes an applicator 12, a mounting unit 14, and an electronicsunit 16. The system can further include a receiver 158, such as isdescribed in more detail with reference to FIG. 15.

The mounting unit (housing) 14 includes a base 24 adapted for mountingon the skin of a host, a sensor adapted for transdermal insertionthrough the skin of a host (see FIG. 4A), and one or more contacts 28configured to provide secure electrical contact between the sensor andthe electronics unit 16. The mounting unit 14 is designed to maintainthe integrity of the sensor in the host so as to reduce or eliminatetranslation of motion between the mounting unit, the host, and/or thesensor.

In one embodiment, an applicator 12 is provided for inserting the sensor32 through the host's skin at the appropriate insertion angle with theaid of a needle (see FIGS. 6 through 8), and for subsequent removal ofthe needle using a continuous push-pull action. Preferably, theapplicator comprises an applicator body 18 that guides the applicatorcomponents (see FIGS. 6 through 8) and includes an applicator body base60 configured to mate with the mounting unit 14 during insertion of thesensor into the host. The mate between the applicator body base 60 andthe mounting unit 14 can use any known mating configuration, forexample, a snap-fit, a press-fit, an interference-fit, or the like, todiscourage separation during use. One or more release latches 30 enablerelease of the applicator body base 60, for example, when the applicatorbody base 60 is snap fit into the mounting unit 14.

The electronics unit 16 includes hardware, firmware, and/or softwarethat enable measurement of levels of the analyte via the sensor. Forexample, the electronics unit 16 can comprise a potentiostat, a powersource for providing power to the sensor, other components useful forsignal processing, and preferably an RF module for transmitting datafrom the electronics unit 16 to a receiver (see FIGS. 14 to 16).Electronics can be affixed to a printed circuit board (PCB), or thelike, and can take a variety of forms. For example, the electronics cantake the form of an integrated circuit (IC), such as anApplication-Specific Integrated Circuit (ASIC), a microcontroller, or aprocessor. Preferably, electronics unit 16 houses the sensorelectronics, which comprise systems and methods for processing sensoranalyte data. Examples of systems and methods for processing sensoranalyte data are described in more detail in U.S. Publication No.US-2005-0027463-A1.

After insertion of the sensor using the applicator 12, and subsequentrelease of the applicator 12 from the mounting unit 14 (see FIGS. 8B to8D), the electronics unit 16 is configured to releasably mate with themounting unit 14 in a manner similar to that described above withreference to the applicator body base 60. The electronics unit 16includes contacts on its backside (not shown) configured to electricallyconnect with the contacts 28, such as are described in more detail withreference to FIGS. 2 through 4. In one embodiment, the electronics unit16 is configured with programming, for example initialization,calibration reset, failure testing, or the like, each time it isinitially inserted into the mounting unit 14 and/or each time itinitially communicates with the sensor 32.

Mounting Unit

FIG. 2 is a perspective view of a sensor system of a preferredembodiment, shown in its functional position, including a mounting unitand an electronics unit matingly engaged therein. FIGS. 12A to 12Cillustrate the sensor is its functional position for measurement of ananalyte concentration in a host.

In preferred embodiments, the mounting unit 14, also referred to as ahousing, comprises a base 24 adapted for fastening to a host's skin. Thebase can be formed from a variety of hard or soft materials, andpreferably comprises a low profile for minimizing protrusion of thedevice from the host during use. In some embodiments, the base 24 isformed at least partially from a flexible material, which is believed toprovide numerous advantages over conventional transcutaneous sensors,which, unfortunately, can suffer from motion-related artifactsassociated with the host's movement when the host is using the device.For example, when a transcutaneous analyte sensor is inserted into thehost, various movements of the sensor (for example, relative movementbetween the in vivo portion and the ex vivo portion, movement of theskin, and/or movement within the host (dermis or subcutaneous)) createstresses on the device and can produce noise in the sensor signal. It isbelieved that even small movements of the skin can translate todiscomfort and/or motion-related artifact, which can be reduced orobviated by a flexible or articulated base. Thus, by providingflexibility and/or articulation of the device against the host's skin,better conformity of the sensor system 10 to the regular use andmovements of the host can be achieved. Flexibility or articulation isbelieved to increase adhesion (with the use of an adhesive pad) of themounting unit 14 onto the skin, thereby decreasing motion-relatedartifact that can otherwise translate from the host's movements andreduced sensor performance.

FIG. 3 is an exploded perspective view of a sensor system of a preferredembodiment, showing a mounting unit, an associated contact subassembly,and an electronics unit. In some embodiments, the contacts 28 aremounted on or in a subassembly hereinafter referred to as a contactsubassembly 26 (see FIG. 4A), which includes a contact holder 34configured to fit within the base 24 of the mounting unit 14 and a hinge38 that allows the contact subassembly 26 to pivot between a firstposition (for insertion) and a second position (for use) relative to themounting unit 14, which is described in more detail with reference toFIGS. 10 and 11. The term “hinge” as used herein is a broad term and isused in its ordinary sense, including, without limitation, to refer toany of a variety of pivoting, articulating, and/or hinging mechanisms,such as an adhesive hinge, a sliding joint, and the like; the term hingedoes not necessarily imply a fulcrum or fixed point about which thearticulation occurs.

In certain embodiments, the mounting unit 14 is provided with anadhesive pad 8, preferably disposed on the mounting unit's back surfaceand preferably including a releasable backing layer 9. Thus, removingthe backing layer 9 and pressing the base portion 24 of the mountingunit onto the host's skin adheres the mounting unit 14 to the host'sskin. Additionally or alternatively, an adhesive pad can be placed oversome or all of the sensor system after sensor insertion is complete toensure adhesion, and optionally to ensure an airtight seal or watertightseal around the wound exit-site (or sensor insertion site) (not shown).Appropriate adhesive pads can be chosen and designed to stretch,elongate, conform to, and/or aerate the region (e.g., host's skin).

In preferred embodiments, the adhesive pad 8 is formed from spun-laced,open- or closed-cell foam, and/or non-woven fibers, and includes anadhesive disposed thereon, however a variety of adhesive padsappropriate for adhesion to the host's skin can be used, as isappreciated by one skilled in the art of medical adhesive pads. In someembodiments, a double-sided adhesive pad is used to adhere the mountingunit to the host's skin. In other embodiments, the adhesive pad includesa foam layer, for example, a layer wherein the foam is disposed betweenthe adhesive pad's side edges and acts as a shock absorber.

In some embodiments, the surface area of the adhesive pad 8 is greaterthan the surface area of the mounting unit's back surface.Alternatively, the adhesive pad can be sized with substantially the samesurface area as the back surface of the base portion. Preferably, theadhesive pad has a surface area on the side to be mounted on the host'sskin that is greater than about 1, 1.25, 1.5, 1.75, 2, 2.25, or 2.5,times the surface area of the back surface 25 of the mounting unit base24. Such a greater surface area can increase adhesion between themounting unit and the host's skin, minimize movement between themounting unit and the host's skin, and/or protect the wound exit-site(sensor insertion site) from environmental and/or biologicalcontamination. In some alternative embodiments, however, the adhesivepad can be smaller in surface area than the back surface assuming asufficient adhesion can be accomplished.

In some embodiments, the adhesive pad 8 is substantially the same shapeas the back surface 25 of the base 24, although other shapes can also beadvantageously employed, for example, butterfly-shaped, round, square,or rectangular. The adhesive pad backing can be designed for two-steprelease, for example, a primary release wherein only a portion of theadhesive pad is initially exposed to allow adjustable positioning of thedevice, and a secondary release wherein the remaining adhesive pad islater exposed to firmly and securely adhere the device to the host'sskin once appropriately positioned. The adhesive pad is preferablywaterproof. Preferably, a stretch-release adhesive pad is provided onthe back surface of the base portion to enable easy release from thehost's skin at the end of the useable life of the sensor, as isdescribed in more detail with reference to FIGS. 9A to 9C.

In some circumstances, it has been found that a conventional bondbetween the adhesive pad and the mounting unit may not be sufficient,for example, due to humidity that can cause release of the adhesive padfrom the mounting unit. Accordingly, in some embodiments, the adhesivepad can be bonded using a bonding agent activated by or accelerated byan ultraviolet, acoustic, radio frequency, or humidity cure. In someembodiments, a eutectic bond of first and second composite materials canform a strong adhesion. In some embodiments, the surface of the mountingunit can be pretreated utilizing ozone, plasma, chemicals, or the like,in order to enhance the bondability of the surface.

A bioactive agent is preferably applied locally at the insertion site(exit-site) prior to or during sensor insertion. Suitable bioactiveagents include those which are known to discourage or prevent bacterialgrowth and infection, for example, anti-inflammatory agents,antimicrobials, antibiotics, or the like. It is believed that thediffusion or presence of a bioactive agent can aid in prevention orelimination of bacteria adjacent to the exit-site. Additionally oralternatively, the bioactive agent can be integral with or coated on theadhesive pad, or no bioactive agent at all is employed.

FIG. 4A is an exploded perspective view of the contact subassembly 26 inone embodiment, showing its individual components. Preferably, awatertight (waterproof or water-resistant) sealing member 36, alsoreferred to as a sealing material or seal, fits within a contact holder34 and provides a watertight seal configured to surround the electricalconnection at the electrode terminals within the mounting unit in orderto protect the electrodes (and the respective operable connection withthe contacts of the electronics unit 16) from damage due to moisture,humidity, dirt, and other external environmental factors. In oneembodiment, the sealing member 36 is formed from an elastomericmaterial, such as silicone; however, a variety of other elastomeric orsealing materials can also be used, for example, silicone-polyurethanehybrids, polyurethanes, and polysulfides. Preferably, the sealing memberis configured to compress within the contact subassembly when theelectronics unit is mated to the mounting unit. In some embodiments, thesealing member 36 comprises a self-lubricating material, for example,self-lubricating silicone or other materials impregnated with orotherwise comprising a lubricant configured to be released during use.In some embodiments, the sealing member 36 includes a self-sealingmaterial, for example, one that leaches out a sealant such as a siliconeoil. In some embodiments, bumps, ridges, or other raised portions (notshown), can be added to a component of the sensor system, such as to thecontact subassembly 26 (e.g., housing adjacent to the sealing member),electronics unit 16 and/or sealing member 36 to provide additionalcompression and improve the seal formed around the contacts 28 and/orsensor 32 when the contacts 28 are mated to the sensor electronics.

Preferably, the sealing member is selected using a durometer. Adurometer is an instrument used for measuring the indentation hardnessof rubber, plastics, and other materials. Durometers are built tovarious standards from ASTM, DIN, JIS, and ISO. The hardness of plasticsis most commonly measured by the Shore (Durometer) test or Rockwellhardness test. Both methods measure the resistance of plastics towardindentation and provide an empirical hardness value. Shore Hardness,using either the Shore A or Shore D scale, is the preferred method forrubbers/elastomers and is also commonly used for softer plastics such aspolyolefins, fluoropolymers, and vinyls. The Shore A scale is used forsofter rubbers while the Shore D scale is used for harder ones. Inpreferred embodiments, the Shore A scale is employed in connection withselection of a sealing member.

The Shore hardness is measured with a Durometer and sometimes referredto as “Durometer hardness.” The hardness value is determined by thepenetration of the Durometer indenter foot into the sample. Because ofthe resilience of rubbers and plastics, the indentation reading maychange over time, so the indentation time is sometimes reported alongwith the hardness number. The ASTM test method designation for the ShoreDurometer hardness test is ASTM D2240. The results obtained from thistest are a useful measure of relative resistance to indentation ofvarious grades of polymers.

Using a durometer in the selection of a sealing member enables selectionof a material with optimal durometer hardness that balances theadvantages of a lower durometer hardness with the advantages of a higherdurometer hardness. For example, when a guide tube (e.g., cannula) isutilized to maintain an opening in a silicone sealing member prior tosensor insertion, a compression set (e.g., some retention of acompressed shape caused by compression of the material over time) withinthe silicone can result due to compression over time of the sealingmember by the guide tube. Compression set can also result from certainsterilization procedures (e.g., radiation sterilization such as electronbeam or gamma radiation). Unfortunately, in some circumstances, thecompression set of the sealing member may cause gaps or incompletenessof contact between the sealing member and the contacts and/or sensor. Ingeneral, a lower durometer hardness provides a better conformation(e.g., seal) surrounding the contacts and/or sensor as compared to ahigher durometer hardness. Additionally, a lower durometer hardnessenables a design wherein less force is required to create the seal(e.g., to snap the electronics unit into the mounting unit, for example,as in the embodiment illustrated in FIG. 4A) as compared to a higherdurometer hardness, thereby increasing the ease of use of the device.However, the benefits of a lower durometer hardness silicone materialmust be balanced with potential disadvantages in manufacturing. Forexample, lower durometer hardness silicones are often produced bycompounding with a silicone oil. In some circumstances, it is believedthat some silicone oil may leach or migrate during manufacture and/orsterilization, which may corrupt aspects of the manufacturing process(e.g., adhesion of glues and/or effectiveness of coating processes).Additionally, a higher durometer hardness material generally providesgreater stability of the material, which may reduce or avoid damage tothe sealing member cause by pressure or other forces.

It is generally preferred that a sealing member 36 with a durometerhardness of from about 5 to about 80 Shore A is employed, morepreferably a durometer hardness of from about 10 to about 50 Shore A,and even more preferably from about 20 to about 50 Shore A. In oneembodiment, of a transcutaneous analyte sensor, the sealing member isfabricated using a silicone of about 20 Shore A to maximize theconformance of the seal around the contacts and/or sensor whileminimizing the force required to compress the silicone for thatconformance. In another embodiment, the sealing member is formed from asilicone of about 50 Shore A so as to provide increased strength of thesealing member (e.g., its resistance to compression). While a fewrepresentative examples have been provided above, one skilled in the artappreciates that higher or lower durometer hardness sealing material mayalso be suitable for use.

In one alternative embodiment, a sealing member 36 with a durometerhardness of about 10 Shore A is used. In this embodiment, the sealingmaterial tends to “weep” out, further increasing conformance of the sealagainst the adjacent parts. In another alternative embodiment, a sealingmaterial with a durometer hardness of about 0 (zero) Shore A is used asa sealant and/or in combination with a sealant, also referred to as alubricant, which in some embodiments is a hydrophobic fluid fillingmaterial such as a grease, silicone, petroleum jelly, or the like.Preferably, the sensor and/or contacts are encased in a housing thatcontains the sealant, causing the material to “squeeze” around contactsand/or sensor. Any suitable hydrophobic fluid filling material can beemployed. Especially preferred are synthetic or petroleumhydrocarbon-based materials, silicone-based materials, ester-basedgreases, and other pharmaceutical-grade materials.

In some embodiments, the sealing member can comprise a material that hasbeen modified to enhance the desirable properties of the sealing member36. For example, one or more filler materials or stiffening agents suchas glass beads, polymer beads, composite beads, beads comprising variousinert materials, carbon black, talc, titanium oxide, silicone dioxide,and the like. In some embodiments, the filler material is incorporatedinto the sealing member material to mechanically stiffen the sealingmember. In general, however, use of a filler material or stiffeningagent in the sealing member material can provide a variety of enhancedproperties including increased modulus of elasticity, crosslink density,hardness, and stiffness, and decreased creep, for example. In somealternative embodiments, gases are chemically (or otherwise) injectedinto the sealing member material. For example, the sealing material cancomprise a polymeric foam (e.g., a polyurethane foam, a latex foam, astyrene-butadiene foam, and the like), or a dispersion of gas bubbles ina grease or jelly.

In alternative embodiments, the seal 36 is designed to form aninterference fit with the electronics unit and can be formed from avariety of materials, for example, flexible plastics, or noble metals.One of ordinary skill in the art appreciates that a variety of designscan be employed to provide a seal surrounding electrical contacts suchas described herein. For example, the contact holder 34 can beintegrally designed as a part of the mounting unit, rather than as aseparate piece thereof. Additionally or alternatively, a sealant can beprovided in or around the sensor (e.g., within or on the contactsubassembly or sealing member), such as is described in more detail withreference to FIGS. 11A and 11B. In general, sealing materials withdurometer hardnesses in the described ranges can provide improvedsealing in a variety of sensor applications. For example, a sealingmember as described in the preferred embodiments (e.g., selected using adurometer to ensure optimal durometer hardness, and the like) can beimplemented adjacent to and/or to at least partially surrounding thesensor in a variety of sensor designs, including, for example, thesensor designs of the preferred embodiments, as well as a planarsubstrate such as described in U.S. Pat. No. 6,175,752.

In the illustrated embodiment of FIG. 4A, the sealing member 36 isformed with a raised portion 37 surrounding the contacts 28. The raisedportion 37 enhances the interference fit surrounding the contacts 28when the electronics unit 16 is mated to the mounting unit 14. Namely,the raised portion surrounds each contact and presses against theelectronics unit 16 to form a tight seal around the electronics unit.However, a variety of alternative sealing member configurations aredescribed with reference to FIGS. 4D to 4H, below.

Contacts 28 fit within the seal 36 and provide for electrical connectionbetween the sensor 32 and the electronics unit 16. In general, thecontacts are designed to ensure a stable mechanical and electricalconnection of the electrodes that form the sensor 32 (see FIG. 5A to 5C)to mutually engaging contacts 28 thereon. A stable connection can beprovided using a variety of known methods, for example, domed metalliccontacts, cantilevered fingers, pogo pins, or the like, as isappreciated by one skilled in the art.

In preferred embodiments, the contacts 28 are formed from a conductiveelastomeric material, such as a carbon black elastomer, through whichthe sensor 32 extends (see FIGS. 10B and 11B). Conductive elastomers areadvantageously employed because their resilient properties create anatural compression against mutually engaging contacts, forming a securepress fit therewith. In some embodiments, conductive elastomers can bemolded in such a way that pressing the elastomer against the adjacentcontact performs a wiping action on the surface of the contact, therebycreating a cleaning action during initial connection. Additionally, inpreferred embodiments, the sensor 32 extends through the contacts 28wherein the sensor is electrically and mechanically secure by therelaxation of elastomer around the sensor (see FIGS. 7A to 7D).

In an alternative embodiment, a conductive, stiff plastic forms thecontacts, which are shaped to comply upon application of pressure (forexample, a leaf-spring shape). Contacts of such a configuration can beused instead of a metallic spring, for example, and advantageously avoidthe need for crimping or soldering through compliant materials;additionally, a wiping action can be incorporated into the design toremove contaminants from the surfaces during connection. Non-metalliccontacts can be advantageous because of their seamlessmanufacturability, robustness to thermal compression, non-corrosivesurfaces, and native resistance to electrostatic discharge (ESD) damagedue to their higher-than-metal resistance.

FIGS. 4B and 4C are perspective views of alternative contactconfigurations. FIG. 4B is an illustration of a narrow contactconfiguration. FIG. 4C is an illustration of a wide contactconfiguration. One skilled in the art appreciates that a variety ofconfigurations are suitable for the contacts of the preferredembodiments, whether elastomeric, stiff plastic or other materials areused. In some circumstances, it can be advantageous to provide multiplecontact configurations (such as illustrated in FIGS. 4A to 4C) todifferentiate sensors from each other. In other words, the architectureof the contacts can include one or more configurations each designed(keyed) to fit with a particular electronics unit. See section entitled“Differentiation of Sensor Systems” below, which describes systems andmethods for differentiating (keying) sensor systems.

FIGS. 4D to 4H are schematic cross-sectional views of a portion of thecontact subassembly; namely, a variety of alternative embodiments of thesealing member 36 are illustrated. In each of these embodiments (e.g.,FIGS. 4D to 4H), a sensor 32 is shown, which is configured for operableconnection to sensor electronics for measuring an analyte in a host suchas described in more detail elsewhere herein. Additionally, twoelectrical contacts 28, as described in more detail elsewhere herein,are configured to operably connect the sensor to the sensor electronics.Thus, the sealing member 36 in each of these alternative configurations(e.g., FIGS. 4D to 4H) at least partially surrounds the sensor and/orthe electrical contacts to seal the electrical contacts from moisturewhen the sensor is operably connected to the sensor electronics.

FIG. 4D is a schematic cross-sectional view of the sealing member 36 inan embodiment similar to FIG. 4A, including gaps 400 that are maintainedwhen the one or more electrical contacts are operably connected to thesensor electronics. Preferably, these air gaps provide for someflexibility of the sealing member 36 to deform or compress to seal theelectrical contacts 28 from moisture or other environmental effects.

In certain circumstances, such as during sensor insertion orneedle/guide tube retraction (see FIGS. 7A to 7D), a sealing member witha certain elasticity can be compressed or deformed by the insertionand/or retraction forces applied thereto. Accordingly in someembodiments, the sealing member is configured to be maintained (e.g.,held substantially in place) on the housing (e.g., contact subassembly26 or base 34) without substantial translation, deformation, and/orcompression (e.g., during sensor insertion). FIG. 4D illustrates onesuch implementation, wherein one or more depressions 402 are configuredto receive mating protrusions (e.g., on the base 34 of the contactsubassembly 26, not shown). A variety of male-female or other suchmechanical structures can be implemented to hold the sealing member inplace, as is appreciated by one skilled in the art. In one alternativeembodiment, an adhesive (not shown) is configured to adhere the sealingmember 36 to the housing (e.g., base 34 of the contact subassembly 26)to provide substantially the same benefit of holding the sealing memberduring sensor insertion/retraction without substantial deformation, asdescribed in more detail, above. In another embodiment, the base 34 ofthe contact subassembly 26 (or equivalent structure) comprisesreinforcing mechanical supports configured to hold the sealing member asdescribed above. One skilled in the art appreciates a variety ofmechanical and/or chemical methods that can be implemented to maintain asealing member substantially stationary (e.g., without substantialtranslation, deformation and/or compression) when compression and/ordeformation forces are applied thereto. Although one exemplaryembodiment is illustrated with reference to FIG. 4D, a wide variety ofsystems and methods for holding the sealing member can be implementedwith a sealing member of any particular design.

FIG. 4E is a schematic cross-sectional view of the sealing member 36 inan alternative embodiment without gaps. In certain circumstances, fullcontact between mating members may be preferred.

In certain circumstances moisture may “wick” along the length of thesensor (e.g., from an exposed end) through the sealing member 36 to thecontacts 28. FIG. 4F is a schematic cross-sectional view of a sealingmember 36 in an alternative embodiment wherein one or more gaps 400 areprovided. In this embodiment, the gaps 400 extend into the sealingmember and encompass at least a portion of the sensor 32. The gaps 400or “deep wells” of FIG. 4F are designed to interrupt the path thatmoisture may take, avoiding contact of the moisture at the contacts 28.If moisture is able to travel along the path of the sensor, the abruptchange of surface tension at the opening 404 of the gap 400 in thesealing member 36 substantially deters the moisture from traveling tothe contacts 28.

FIG. 4G is a schematic cross-sectional view of the sealing member 36 inanother alternative embodiment wherein one or more gaps 400 areprovided. In this embodiment, the gaps extend from the bottom side ofthe sealing member 36, which can be helpful in maintaining a stableposition of the contacts 28 and/or reduces “pumping” of air gaps in somesituations.

In some embodiments, gaps 400 can be filled by a sealant, which also maybe referred to as a lubricant, for example, oil, grease, or gel. In oneexemplary embodiment, the sealant includes petroleum jelly and is usedto provide a moisture barrier surrounding the sensor. Referring to FIG.4F, filling the gaps 400 with a sealant provides an additional moisturebarrier to reduce or avoid moisture from traveling to the contacts 28.Sealant can be used to fill gaps or crevices in any sealing memberconfiguration.

In some sealing member configurations, it can be advantageous to providea channel 406 through the sealing member 36 in order to create anadditional pathway for sealant (e.g. lubricant) in order to expel airand/or to provide a path for excess sealant to escape. In someembodiments, more than one channel is provided.

FIG. 4H is a schematic cross-sectional view of a sealing member 36 in analternative embodiment wherein a large gap 400 is provided between thesealing member upper portion 408 and the sealing member lower portion410. These portions 408, 410 may or may be connected; however, they areconfigured to sandwich the sensor and sealant (e.g., grease)therebetween. The sealing member 36 illustrated with reference to FIG.4H can provide ease of manufacture and/or product assembly with acomprehensive sealing ability. Additional gaps (with or without sealant)can be provided in a variety of locations throughout the sealing member36; these additional gaps, for example, provide space for excesssealant.

Sensor

Preferably, the sensor 32 includes a distal portion 42, also referred toas the in vivo portion, adapted to extend out of the mounting unit forinsertion under the host's skin, and a proximal portion 40, alsoreferred to as an ex vivo portion, adapted to remain above the host'sskin after sensor insertion and to operably connect to the electronicsunit 16 via contacts 28. Preferably, the sensor 32 includes two or moreelectrodes: a working electrode 44 and at least one additionalelectrode, which can function as a counter electrode and/or referenceelectrode, hereinafter referred to as the reference electrode 46. Amembrane system is preferably deposited over the electrodes, such asdescribed in more detail with reference to FIGS. 5A to 5C, below.

FIG. 5A is an expanded cutaway view of a proximal portion 40 of thesensor in one embodiment, showing working and reference electrodes. Inthe illustrated embodiments, the working and reference electrodes 44, 46extend through the contacts 28 to form electrical connection therewith(see FIGS. 10B and 11B). Namely, the working electrode 44 is inelectrical contact with one of the contacts 28 and the referenceelectrode 46 is in electrical contact with the other contact 28, whichin turn provides for electrical connection with the electronics unit 16when it is mated with the mounting unit 14. Mutually engaging electricalcontacts permit operable connection of the sensor 32 to the electronicsunit 16 when connected to the mounting unit 14; however other methods ofelectrically connecting the electronics unit 16 to the sensor 32 arealso possible. In some alternative embodiments, for example, thereference electrode can be configured to extend from the sensor andconnect to a contact at another location on the mounting unit (e.g.,non-coaxially). Detachable connection between the mounting unit 14 andelectronics unit 16 provides improved manufacturability, namely, therelatively inexpensive mounting unit 14 can be disposed of whenreplacing the sensor system after its usable life, while the relativelymore expensive electronics unit 16 can be reused with multiple sensorsystems.

In alternative embodiments, the contacts 28 are formed into a variety ofalternative shapes and/or sizes. For example, the contacts 28 can bediscs, spheres, cuboids, and the like. Furthermore, the contacts 28 canbe designed to extend from the mounting unit in a manner that causes aninterference fit within a mating cavity or groove of the electronicsunit, forming a stable mechanical and electrical connection therewith.

FIG. 5B is an expanded cutaway view of a distal portion of the sensor inone embodiment, showing working and reference electrodes. In preferredembodiments, the sensor is formed from a working electrode 44 and areference electrode 46 helically wound around the working electrode 44.An insulator 45 is disposed between the working and reference electrodesto provide necessary electrical insulation therebetween. Certainportions of the electrodes are exposed to enable electrochemicalreaction thereon, for example, a window 43 can be formed in theinsulator to expose a portion of the working electrode 44 forelectrochemical reaction.

In preferred embodiments, each electrode is formed from a fine wire witha diameter of from about 0.001 or less to about 0.010 inches or more,for example, and is formed from, e.g., a plated insulator, a platedwire, or bulk electrically conductive material. Although the illustratedelectrode configuration and associated text describe one preferredmethod of forming a transcutaneous sensor, a variety of knowntranscutaneous sensor configurations can be employed with thetranscutaneous analyte sensor system of the preferred embodiments, suchas U.S. Pat. No. 5,711,861 to Ward et al., U.S. Pat. No. 6,642,015 toVachon et al., U.S. Pat. No. 6,654,625 to Say et al., U.S. Pat. No.6,565,509 to Say et al., U.S. Pat. No. 6,514,718 to Heller, U.S. Pat.No. 6,465,066 to Essenpreis et al., U.S. Pat. No. 6,214,185 toOffenbacher et al., U.S. Pat. No. 5,310,469 to Cunningham et al., andU.S. Pat. No. 5,683,562 to Shaffer et al., U.S. Pat. No. 6,579,690 toBonnecaze et al., U.S. Pat. No. 6,484,046 to Say et al., U.S. Pat. No.6,512,939 to Colvin et al., U.S. Pat. No. 6,424,847 to Mastrototaro etal., U.S. Pat. No. 6,424,847 to Mastrototaro et al, for example. All ofthe above patents are incorporated in their entirety herein by referenceand are not inclusive of all applicable analyte sensors; in general, itshould be understood that the disclosed embodiments are applicable to avariety of analyte sensor configurations. It is noted that much of thedescription of the preferred embodiments, for example the membranesystem described below, can be implemented not only with in vivosensors, but also with in vitro sensors, such as blood glucose meters(SMBG).

In preferred embodiments, the working electrode comprises a wire formedfrom a conductive material, such as platinum, platinum-iridium,palladium, graphite, gold, carbon, conductive polymer, alloys, or thelike. Although the electrodes can by formed by a variety ofmanufacturing techniques (bulk metal processing, deposition of metalonto a substrate, or the like), it can be advantageous to form theelectrodes from plated wire (e.g., platinum on steel wire) or bulk metal(e.g., platinum wire). It is believed that electrodes formed from bulkmetal wire provide superior performance (e.g., in contrast to depositedelectrodes), including increased stability of assay, simplifiedmanufacturability, resistance to contamination (e.g., which can beintroduced in deposition processes), and improved surface reaction(e.g., due to purity of material) without peeling or delamination.

The working electrode 44 is configured to measure the concentration ofan analyte. In an enzymatic electrochemical sensor for detectingglucose, for example, the working electrode measures the hydrogenperoxide produced by an enzyme catalyzed reaction of the analyte beingdetected and creates a measurable electronic current For example, in thedetection of glucose wherein glucose oxidase produces hydrogen peroxideas a byproduct, hydrogen peroxide reacts with the surface of the workingelectrode producing two protons (2H⁺), two electrons (2e⁻) and onemolecule of oxygen (O₂), which produces the electronic current beingdetected.

In preferred embodiments, the working electrode 44 is covered with aninsulating material 45, for example, a non-conductive polymer.Dip-coating, spray-coating, vapor-deposition, or other coating ordeposition techniques can be used to deposit the insulating material onthe working electrode. In one embodiment, the insulating materialcomprises parylene, which can be an advantageous polymer coating for itsstrength, lubricity, and electrical insulation properties. Generally,parylene is produced by vapor deposition and polymerization ofpara-xylylene (or its substituted derivatives). While not wishing to bebound by theory, it is believed that the lubricious (e.g., smooth)coating (e.g., parylene) on the sensors of the preferred embodimentscontributes to minimal trauma and extended sensor life. FIG. 23 showstranscutaneous glucose sensor data and corresponding blood glucosevalues over approximately seven days in a human, wherein thetranscutaneous glucose sensor data was formed with a parylene coating onat least a portion of the device. While parylene coatings are generallypreferred, any suitable insulating material can be used, for example,fluorinated polymers, polyethyleneterephthalate, polyurethane,polyimide, other nonconducting polymers, or the like. Glass or ceramicmaterials can also be employed. Other materials suitable for use includesurface energy modified coating systems such as are marketed under thetrade names AMC18, AMC148, AMC141, and AMC321 by Advanced MaterialsComponents Express of Bellafonte, PA. In some alternative embodiments,however, the working electrode may not require a coating of insulator.

The reference electrode 46, which can function as a reference electrodealone, or as a dual reference and counter electrode, is formed fromsilver, silver/silver chloride, or the like. Preferably, the referenceelectrode 46 is juxtapositioned and/or twisted with or around theworking electrode 44; however other configurations are also possible(e.g., an intradermal or on-skin reference electrode). In theillustrated embodiments, the reference electrode 46 is helically woundaround the working electrode 44. The assembly of wires is thenoptionally coated or adhered together with an insulating material,similar to that described above, so as to provide an insulatingattachment.

In some embodiments, a silver wire is formed onto the sensor asdescribed above, and subsequently chloridized to form silver/silverchloride reference electrode. Advantageously, chloridizing the silverwire as described herein enables the manufacture of a referenceelectrode with optimal in vivo performance. Namely, by controlling thequantity and amount of chloridization of the silver to formsilver/silver chloride, improved break-in time, stability of thereference electrode, and extended life has been shown with the preferredembodiments (see FIGS. 22 and 23). Additionally, use of silver chlorideas described above allows for relatively inexpensive and simplemanufacture of the reference electrode.

In embodiments wherein an outer insulator is disposed, a portion of thecoated assembly structure can be stripped or otherwise removed, forexample, by hand, excimer lasing, chemical etching, laser ablation,grit-blasting (e.g., with sodium bicarbonate or other suitable grit), orthe like, to expose the electroactive surfaces. Alternatively, a portionof the electrode can be masked prior to depositing the insulator inorder to maintain an exposed electroactive surface area. In oneexemplary embodiment, grit blasting is implemented to expose theelectroactive surfaces, preferably utilizing a grit material that issufficiently hard to ablate the polymer material, while beingsufficiently soft so as to minimize or avoid damage to the underlyingmetal electrode (e.g., a platinum electrode). Although a variety of“grit” materials can be used (e.g., sand, talc, walnut shell, groundplastic, sea salt, and the like), in some preferred embodiments, sodiumbicarbonate is an advantageous grit-material because it is sufficientlyhard to ablate, e.g., a parylene coating without damaging, e.g., anunderlying platinum conductor. One additional advantage of sodiumbicarbonate blasting includes its polishing action on the metal as itstrips the polymer layer, thereby eliminating a cleaning step that mightotherwise be necessary.

In the embodiment illustrated in FIG. 5B, a radial window 43 is formedthrough the insulating material 45 to expose a circumferentialelectroactive surface of the working electrode. Additionally, sections41 of electroactive surface of the reference electrode are exposed. Forexample, the 41 sections of electroactive surface can be masked duringdeposition of an outer insulating layer or etched after deposition of anouter insulating layer.

In some applications, cellular attack or migration of cells to thesensor can cause reduced sensitivity and/or function of the device,particularly after the first day of implantation. However, when theexposed electroactive surface is distributed circumferentially about thesensor (e.g., as in a radial window), the available surface area forreaction can be sufficiently distributed so as to minimize the effect oflocal cellular invasion of the sensor on the sensor signal.Alternatively, a tangential exposed electroactive window can be formed,for example, by stripping only one side of the coated assemblystructure. In other alternative embodiments, the window can be providedat the tip of the coated assembly structure such that the electroactivesurfaces are exposed at the tip of the sensor. Other methods andconfigurations for exposing electroactive surfaces can also be employed.

In some embodiments, the working electrode has a diameter of from about0.001 inches or less to about 0.010 inches or more, preferably fromabout 0.002 inches to about 0.008 inches, and more preferably from about0.004 inches to about 0.005 inches. The length of the window can be fromabout 0.1 mm (about 0.004 inches) or less to about 2 mm (about 0.078inches) or more, and preferably from about 0.5 mm (about 0.02 inches) toabout 0.75 mm (0.03 inches). In such embodiments, the exposed surfacearea of the working electrode is preferably from about 0.000013 in(0.0000839 cm²) or less to about 0.0025 in2 (0.016129 cm²) or more(assuming a diameter of from about 0.001 inches to about 0.010 inchesand a length of from about 0.004 inches to about 0.078 inches). Thepreferred exposed surface area of the working electrode is selected toproduce an analyte signal with a current in the picoAmp range, such asis described in more detail elsewhere herein. However, a current in thepicoAmp range can be dependent upon a variety of factors, for examplethe electronic circuitry design (e.g., sample rate, current draw, A/Dconverter bit resolution, etc.), the membrane system (e.g., permeabilityof the analyte through the membrane system), and the exposed surfacearea of the working electrode. Accordingly, the exposed electroactiveworking electrode surface area can be selected to have a value greaterthan or less than the above-described ranges taking into considerationalterations in the membrane system and/or electronic circuitry. Inpreferred embodiments of a glucose sensor, it can be advantageous tominimize the surface area of the working electrode while maximizing thediffusivity of glucose in order to optimize the signal-to-noise ratiowhile maintaining sensor performance in both high and low glucoseconcentration ranges.

In some alternative embodiments, the exposed surface area of the working(and/or other) electrode can be increased by altering the cross-sectionof the electrode itself. For example, in some embodiments thecross-section of the working electrode can be defined by a cross, star,cloverleaf, ribbed, dimpled, ridged, irregular, or other non-circularconfiguration; thus, for any predetermined length of electrode, aspecific increased surface area can be achieved (as compared to the areaachieved by a circular cross-section). Increasing the surface area ofthe working electrode can be advantageous in providing an increasedsignal responsive to the analyte concentration, which in turn can behelpful in improving the signal-to-noise ratio, for example.

In some alternative embodiments, additional electrodes can be includedwithin the assembly, for example, a three-electrode system (working,reference, and counter electrodes) and/or an additional workingelectrode (e.g., an electrode which can be used to generate oxygen,which is configured as a baseline subtracting electrode, or which isconfigured for measuring additional analytes). U.S. Publication No.US-2005-0161346-A1 and U.S. Publication No. US-2005-0143635-A1 describesome systems and methods for implementing and using additional working,counter, and/or reference electrodes. In one implementation wherein thesensor comprises two working electrodes, the two working electrodes arejuxtapositioned (e.g., extend parallel to each other), around which thereference electrode is disposed (e.g., helically wound). In someembodiments wherein two or more working electrodes are provided, theworking electrodes can be formed in a double-, triple-, quad-, etc.helix configuration along the length of the sensor (for example,surrounding a reference electrode, insulated rod, or other supportstructure). The resulting electrode system can be configured with anappropriate membrane system, wherein the first working electrode isconfigured to measure a first signal comprising glucose and baseline andthe additional working electrode is configured to measure a baselinesignal consisting of baseline only (e.g., configured to be substantiallysimilar to the first working electrode without an enzyme disposedthereon). In this way, the baseline signal can be subtracted from thefirst signal to produce a glucose-only signal that is substantially notsubject to fluctuations in the baseline and/or interfering species onthe signal.

Although the preferred embodiments illustrate one electrodeconfiguration including one bulk metal wire helically wound aroundanother bulk metal wire, other electrode configurations are alsocontemplated. In an alternative embodiment, the working electrodecomprises a tube with a reference electrode disposed or coiled inside,including an insulator therebetween. Alternatively, the referenceelectrode comprises a tube with a working electrode disposed or coiledinside, including an insulator therebetween. In another alternativeembodiment, a polymer (e.g., insulating) rod is provided, wherein theelectrodes are deposited (e.g., electro-plated) thereon. In yet anotheralternative embodiment, a metallic (e.g., steel) rod is provided, coatedwith an insulating material, onto which the working and referenceelectrodes are deposited. In yet another alternative embodiment, one ormore working electrodes are helically wound around a referenceelectrode.

Preferably, the electrodes and membrane systems of the preferredembodiments are coaxially formed, namely, the electrodes and/or membranesystem all share the same central axis. While not wishing to be bound bytheory, it is believed that a coaxial design of the sensor enables asymmetrical design without a preferred bend radius. Namely, in contrastto prior art sensors comprising a substantially planar configurationthat can suffer from regular bending about the plane of the sensor, thecoaxial design of the preferred embodiments do not have a preferred bendradius and therefore are not subject to regular bending about aparticular plane (which can cause fatigue failures and the like).However, non-coaxial sensors can be implemented with the sensor systemof the preferred embodiments.

In addition to the above-described advantages, the coaxial sensor designof the preferred embodiments enables the diameter of the connecting endof the sensor (proximal portion) to be substantially the same as that ofthe sensing end (distal portion) such that the needle is able to insertthe sensor into the host and subsequently slide back over the sensor andrelease the sensor from the needle, without slots or other complexmulti-component designs.

In one such alternative embodiment, the two wires of the sensor are heldapart and configured for insertion into the host in proximal butseparate locations. The separation of the working and referenceelectrodes in such an embodiment can provide additional electrochemicalstability with simplified manufacture and electrical connectivity. It isappreciated by one skilled in the art that a variety of electrodeconfigurations can be implemented with the preferred embodiments.

In some embodiments, the sensor includes an antimicrobial portionconfigured to extend through the exit-site when the sensor is implantedin the host. Namely, the sensor is designed with in vivo and ex vivoportions as described in more detail elsewhere herein; additionally, thesensor comprises a transition portion, also referred to as anantimicrobial portion, located between the in vivo and ex vivo portions42, 40. The antimicrobial portion is designed to provide antimicrobialeffects to the exit-site and adjacent tissue when implanted in the host.

In some embodiments, the antimicrobial portion comprises silver, e.g.,the portion of a silver reference electrode that is configured to extendthrough the exit-site when implanted. Although exit-site infections area common adverse occurrence associated with some conventionaltranscutaneous medical devices, the devices of preferred embodiments aredesigned at least in part to minimize infection, to minimize irritation,and/or to extend the duration of implantation of the sensor by utilizinga silver reference electrode to extend through the exit-site whenimplanted in a patient. While not wishing to be bound by theory, it isbelieved that the silver may reduce local tissue infections (within thetissue and at the exit-site); namely, steady release of molecularquantities of silver is believed to have an antimicrobial effect inbiological tissue (e.g., reducing or preventing irritation andinfection), also referred to as passive antimicrobial effects. Althoughone example of passive antimicrobial effects is described herein, oneskilled in the art can appreciate a variety of passive anti-microbialsystems and methods that can be implemented with the preferredembodiments. Additionally, it is believed that antimicrobial effects cancontribute to extended life of a transcutaneous analyte sensor, enablinga functional lifetime past a few days, e.g., seven days or longer. FIG.23 shows transcutaneous glucose sensor data and corresponding bloodglucose values over approximately seven days in a human, wherein thetranscutaneous glucose sensor data was formed with a silver transitionportion that extended through the exit-site after sensor implantation.

In some embodiments, active antimicrobial systems and methods areprovided in the sensor system in order to further enhance theantimicrobial effects at the exit-site. In one such embodiment, anauxiliary silver wire is disposed on or around the sensor, wherein theauxiliary silver wire is connected to electronics and configured to passa current sufficient to enhance its antimicrobial properties (activeantimicrobial effects), as is appreciated by one skilled in the art. Thecurrent can be passed continuously or intermittently, such thatsufficient antimicrobial properties are provided. Although one exampleof active antimicrobial effects is described herein, one skilled in theart can appreciate a variety of active anti-microbial systems andmethods that can be implemented with the preferred embodiments.

Anchoring Mechanism

It is preferred that the sensor remains substantially stationary withinthe tissue of the host, such that migration or motion of the sensor withrespect to the surrounding tissue is minimized. Migration or motion isbelieved to cause inflammation at the sensor implant site due toirritation, and can also cause noise on the sensor signal due tomotion-related artifact, for example. Therefore, it can be advantageousto provide an anchoring mechanism that provides support for the sensor'sin vivo portion to avoid the above-mentioned problems. Combiningadvantageous sensor geometry with an advantageous anchoring minimizesadditional parts and allows for an optimally small or low profile designof the sensor. In one embodiment the sensor includes a surfacetopography, such as the helical surface topography provided by thereference electrode surrounding the working electrode. In alternativeembodiments, a surface topography could be provided by a roughenedsurface, porous surface (e.g. porous parylene), ridged surface, or thelike. Additionally (or alternatively), the anchoring can be provided byprongs, spines, barbs, wings, hooks, a bulbous portion (for example, atthe distal end), an S-bend along the sensor, a rough surface topography,a gradually changing diameter, combinations thereof, or the like, whichcan be used alone or in combination with the helical surface topographyto stabilize the sensor within the subcutaneous tissue.

Variable Stiffness

As described above, conventional transcutaneous devices are believed tosuffer from motion artifact associated with host movement when the hostis using the device. For example, when a transcutaneous analyte sensoris inserted into the host, various movements on the sensor (for example,relative movement within and between the subcutaneous space, dermis,skin, and external portions of the sensor) create stresses on thedevice, which is known to produce artifacts on the sensor signal.Accordingly, there are different design considerations (for example,stress considerations) on various sections of the sensor. For example,the distal portion 42 of the sensor can benefit in general from greaterflexibility as it encounters greater mechanical stresses caused bymovement of the tissue within the patient and relative movement betweenthe in vivo and ex vivo portions of the sensor. On the other hand, theproximal portion 40 of the sensor can benefit in general from a stiffer,more robust design to ensure structural integrity and/or reliableelectrical connections. Additionally, in some embodiments wherein aneedle is retracted over the proximal portion 40 of the device (seeFIGS. 6 to 8), a stiffer design can minimize crimping of the sensorand/or ease in retraction of the needle from the sensor. Thus, bydesigning greater flexibility into the in vivo (distal) portion 42, theflexibility is believed to compensate for patient movement, and noiseassociated therewith. By designing greater stiffness into the ex vivo(proximal) portion 40, column strength (for retraction of the needleover the sensor), electrical connections, and integrity can be enhanced.In some alternative embodiments, a stiffer distal end and/or a moreflexible proximal end can be advantageous as described in U.S.Publication No. US-2006-0015024-A1.

The preferred embodiments provide a distal portion 42 of the sensor 32designed to be more flexible than a proximal portion 40 of the sensor.The variable stiffness of the preferred embodiments can be provided byvariable pitch of any one or more helically wound wires of the device,variable cross-section of any one or more wires of the device, and/orvariable hardening and/or softening of any one or more wires of thedevice, such as is described in more detail with reference to U.S.Publication No. US-2006-0015024-A1.

Membrane System

FIG. 5C is a cross-sectional view through the sensor on line C-C of FIG.5B showing the exposed electroactive surface of the working electrodesurrounded by the membrane system in one embodiment. Preferably, amembrane system is deposited over at least a portion of theelectroactive surfaces of the sensor 32 (working electrode andoptionally reference electrode) and provides protection of the exposedelectrode surface from the biological environment, diffusion resistance(limitation) of the analyte if needed, a catalyst for enabling anenzymatic reaction, limitation or blocking of interferents, and/orhydrophilicity at the electrochemically reactive surfaces of the sensorinterface. Some examples of suitable membrane systems are described inU.S. Publication No. US-2005-0245799-A1.

In general, the membrane system includes a plurality of domains, forexample, an electrode domain 47, an interference domain 48, an enzymedomain 49 (for example, including glucose oxidase), and a resistancedomain 50, as shown in FIG. 5C, and can include a high oxygen solubilitydomain, and/or a bioprotective domain (not shown), such as is describedin more detail in U.S. Publication No. US-2005-0245799-A1, and such asis described in more detail below. The membrane system can be depositedon the exposed electroactive surfaces using known thin film techniques(for example, vapor deposition, spraying, electro-depositing, dipping,or the like). In alternative embodiments, however, other vapordeposition processes (e.g., physical and/or chemical vapor depositionprocesses) can be useful for providing one or more of the insulatingand/or membrane layers, including ultrasonic vapor deposition,electrostatic deposition, evaporative deposition, deposition bysputtering, pulsed laser deposition, high velocity oxygen fueldeposition, thermal evaporator deposition, electron beam evaporatordeposition, deposition by reactive sputtering molecular beam epitaxy,atmospheric pressure chemical vapor deposition (CVD), atomic layer CVD,hot wire CVD, low-pressure CVD, microwave plasma-assisted CVD,plasma-enhanced CVD, rapid thermal CVD, remote plasma-enhanced CVD, andultra-high vacuum CVD, for example. However, the membrane system can bedisposed over (or deposited on) the electroactive surfaces using anyknown method, as will be appreciated by one skilled in the art.

In some embodiments, one or more domains of the membrane systems areformed from materials such as described above in connection with theporous layer, such as silicone, polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutyleneterephthalate (PBT), polymethylmethacrylate (PMMA), polyether etherketone (PEEK), polyurethanes, cellulosic polymers, polysulfones andblock copolymers thereof including, for example, di-block, tri-block,alternating, random and graft copolymers. U.S. Publication No.US-2005-0245799-A1 describes biointerface and membrane systemconfigurations and materials that may be applied to the preferredembodiments.

Electrode Domain

In selected embodiments, the membrane system comprises an electrodedomain. The electrode domain 47 is provided to ensure that anelectrochemical reaction occurs between the electroactive surfaces ofthe working electrode and the reference electrode, and thus theelectrode domain 47 is preferably situated more proximal to theelectroactive surfaces than the interference and/or enzyme domain.Preferably, the electrode domain includes a coating that maintains alayer of water at the electrochemically reactive surfaces of the sensor.In other words, the electrode domain is present to provide anenvironment between the surfaces of the working electrode and thereference electrode which facilitates an electrochemical reactionbetween the electrodes. For example, a humectant in a binder materialcan be employed as an electrode domain; this allows for the fulltransport of ions in the aqueous environment. The electrode domain canalso assist in stabilizing the operation of the sensor by acceleratingelectrode start-up and drifting problems caused by inadequateelectrolyte. The material that forms the electrode domain can alsoprovide an environment that protects against pH-mediated damage that canresult from the formation of a large pH gradient due to theelectrochemical activity of the electrodes.

In one embodiment, the electrode domain 47 includes a flexible,water-swellable, hydrogel film having a “dry film” thickness of fromabout 0.05 micron or less to about 20 microns or more, more preferablyfrom about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably stillfrom about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. “Dryfilm” thickness refers to the thickness of a cured film cast from acoating formulation by standard coating techniques.

In certain embodiments, the electrode domain 47 is formed of a curablemixture of a urethane polymer and a hydrophilic polymer. Particularlypreferred coatings are formed of a polyurethane polymer havingcarboxylate or hydroxyl functional groups and non-ionic hydrophilicpolyether segments, wherein the polyurethane polymer is crosslinked witha water soluble carbodiimide (e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the presence ofpolyvinylpyrrolidone and cured at a moderate temperature of about 50° C.

In some preferred embodiments, the electrode domain 47 is formed from ahydrophilic polymer such as polyvinylpyrrolidone (PVP). An electrodedomain formed from PVP has been shown to reduce break-in time of analytesensors; for example, a glucose sensor utilizing a cellulosic-basedinterference domain such as described in more detail below.

Preferably, the electrode domain is deposited by vapor deposition, spraycoating, dip coating, or other thin film techniques on the electroactivesurfaces of the sensor. In one preferred embodiment, the electrodedomain is formed by dip-coating the electroactive surfaces in anelectrode layer solution and curing the domain for a time of from about15 minutes to about 30 minutes at a temperature of from about 40° C. toabout 55° C. (and can be accomplished under vacuum (e.g., 20 to 30mmHg)). In embodiments wherein dip-coating is used to deposit theelectrode domain, a preferred insertion rate of from about 1 to about 3inches per minute into the electrode layer solution, with a preferreddwell time of from about 0.5 to about 2 minutes in the electrode layersolution, and a preferred withdrawal rate of from about 0.25 to about 2inches per minute from the electrode layer solution provide a functionalcoating. However, values outside of those set forth above can beacceptable or even desirable in certain embodiments, for example,depending upon solution viscosity and solution surface tension, as isappreciated by one skilled in the art. In one embodiment, theelectroactive surfaces of the electrode system are dip-coated one time(one layer) and cured at 50° C. under vacuum for 20 minutes.

Although an independent electrode domain 47 is described herein, in someembodiments sufficient hydrophilicity can be provided in theinterference domain and/or enzyme domain (the domain adjacent to theelectroactive surfaces) so as to provide for the full transport of ionsin the aqueous environment (e.g. without a distinct electrode domain).In these embodiments, an electrode domain is not necessary.

Interference Domain

Interferents are molecules or other species that are reduced or oxidizedat the electrochemically reactive surfaces of the sensor, eitherdirectly or via an electron transfer agent, to produce a false positiveanalyte signal. In preferred embodiments, an interference domain 48 isprovided that substantially restricts, resists, or blocks the flow ofone or more interfering species. Some known interfering species for aglucose sensor, as described in more detail above, includeacetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine,dopamine, ephedrine, ibuprofen, L-dopa, methyl dopa, salicylate,tetracycline, tolazamide, tolbutamide, triglycerides, and uric acid. Ingeneral, the interference domain of the preferred embodiments is lesspermeable to one or more of the interfering species than to the analyte,e.g., glucose.

In one embodiment, the interference domain 48 is formed from one or morecellulosic derivatives. In general, cellulosic derivatives includepolymers such as cellulose acetate, cellulose acetate butyrate,2-hydroxyethyl cellulose, cellulose acetate phthalate, cellulose acetatepropionate, cellulose acetate trimellitate, and the like.

In one preferred embodiment, the interference domain 48 is formed fromcellulose acetate butyrate. Cellulose acetate butyrate with a molecularweight of about 10,000 daltons to about 75,000 daltons, preferably fromabout 15,000, 20,000, or 25,000 daltons to about 50,000, 55,000, 60,000,65,000, or 70,000 daltons, and more preferably about 20,000 daltons isemployed. In certain embodiments, however, higher or lower molecularweights can be preferred. Additionally, a casting solution or dispersionof cellulose acetate butyrate at a weight percent of about 15% to about25%, preferably from about 15%, 16%, 17%, 18%, 19% to about 20%, 21%,22%, 23%, 24% or 25%, and more preferably about 18% is preferred.Preferably, the casting solution includes a solvent or solvent system,for example an acetone:ethanol solvent system. Higher or lowerconcentrations can be preferred in certain embodiments. A plurality oflayers of cellulose acetate butyrate can be advantageously combined toform the interference domain in some embodiments, for example, threelayers can be employed. It can be desirable to employ a mixture ofcellulose acetate butyrate components with different molecular weightsin a single solution, or to deposit multiple layers of cellulose acetatebutyrate from different solutions comprising cellulose acetate butyrateof different molecular weights, different concentrations, and/ordifferent chemistries (e.g., functional groups). It can also bedesirable to include additional substances in the casting solutions ordispersions, e.g., functionalizing agents, crosslinking agents, otherpolymeric substances, substances capable of modifying thehydrophilicity/hydrophobicity of the resulting layer, and the like.

In one alternative embodiment, the interference domain 48 is formed fromcellulose acetate. Cellulose acetate with a molecular weight of about30,000 daltons or less to about 100,000 daltons or more, preferably fromabout 35,000, 40,000, or 45,000 daltons to about 55,000, 60,000, 65,000,70,000, 75,000, 80,000, 85,000, 90,000, or 95,000 daltons, and morepreferably about 50,000 daltons is preferred. Additionally, a castingsolution or dispersion of cellulose acetate at a weight percent of about3% to about 10%, preferably from about 3.5%, 4.0%, 4.5%, 5.0%, 5.5%,6.0%, or 6.5% to about 7.5%, 8.0%, 8.5%, 9.0%, or 9.5%, and morepreferably about 8% is preferred. In certain embodiments, however,higher or lower molecular weights and/or cellulose acetate weightpercentages can be preferred. It can be desirable to employ a mixture ofcellulose acetates with molecular weights in a single solution, or todeposit multiple layers of cellulose acetate from different solutionscomprising cellulose acetates of different molecular weights, differentconcentrations, or different chemistries (e.g., functional groups). Itcan also be desirable to include additional substances in the castingsolutions or dispersions such as described in more detail above.

Layer(s) prepared from combinations of cellulose acetate and celluloseacetate butyrate, or combinations of layer(s) of cellulose acetate andlayer(s) of cellulose acetate butyrate can also be employed to form theinterference domain 48.

In some alternative embodiments, additional polymers, such as Nafion®,can be used in combination with cellulosic derivatives to provideequivalent and/or enhanced function of the interference domain 48. Asone example, a 5 wt % Nafion® casting solution or dispersion can be usedin combination with a 8 wt % cellulose acetate casting solution ordispersion, e.g., by dip coating at least one layer of cellulose acetateand subsequently dip coating at least one layer Nafion® onto aneedle-type sensor such as described with reference to the preferredembodiments. Any number of coatings or layers formed in any order may besuitable for forming the interference domain of the preferredembodiments.

In some alternative embodiments, more than one cellulosic derivative canbe used to form the interference domain 48 of the preferred embodiments.In general, the formation of the interference domain on a surfaceutilizes a solvent or solvent system in order to solvate the cellulosicderivative (or other polymer) prior to film formation thereon. Inpreferred embodiments, acetone and ethanol are used as solvents forcellulose acetate; however one skilled in the art appreciates thenumerous solvents that are suitable for use with cellulosic derivatives(and other polymers). Additionally, one skilled in the art appreciatesthat the preferred relative amounts of solvent can be dependent upon thecellulosic derivative (or other polymer) used, its molecular weight, itsmethod of deposition, its desired thickness, and the like. However, apercent solute of from about 1% to about 25% is preferably used to formthe interference domain solution so as to yield an interference domainhaving the desired properties. The cellulosic derivative (or otherpolymer) used, its molecular weight, method of deposition, and desiredthickness can be adjusted, depending upon one or more other of theparameters, and can be varied accordingly as is appreciated by oneskilled in the art.

In some alternative embodiments, other polymer types that can beutilized as a base material for the interference domain 48 includingpolyurethanes, polymers having pendant ionic groups, and polymers havingcontrolled pore size, for example. In one such alternative embodiment,the interference domain includes a thin, hydrophobic membrane that isnon-swellable and restricts diffusion of low molecular weight species.The interference domain 48 is permeable to relatively low molecularweight substances, such as hydrogen peroxide, but restricts the passageof higher molecular weight substances, including glucose and ascorbicacid. Other systems and methods for reducing or eliminating interferencespecies that can be applied to the membrane system of the preferredembodiments are described in U.S. Publication No. US-2005-0115832-A1,U.S. Publication No. US-2005-0176136-A1, U.S. Publication No.US-2005-0161346-A1, and U.S. Publication No. US-2005-0143635-A1. In somealternative embodiments, a distinct interference domain is not included.

In preferred embodiments, the interference domain 48 is depositeddirectly onto the electroactive surfaces of the sensor for a domainthickness of from about 0.05 micron or less to about 20 microns or more,more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4,0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and morepreferably still from about 1, 1.5 or 2 microns to about 2.5 or 3microns. Thicker membranes can also be desirable in certain embodiments,but thinner membranes are generally preferred because they have a lowerimpact on the rate of diffusion of hydrogen peroxide from the enzymemembrane to the electrodes.

In general, the membrane systems of the preferred embodiments can beformed and/or deposited on the exposed electroactive surfaces (e.g., oneor more of the working and reference electrodes) using known thin filmtechniques (for example, casting, spray coating, drawing down,electro-depositing, dip coating, and the like), however casting or otherknown application techniques can also be utilized. Preferably, theinterference domain is deposited by vapor deposition, spray coating, ordip coating. In one exemplary embodiment of a needle-type(transcutaneous) sensor such as described herein, the interferencedomain is formed by dip coating the sensor into an interference domainsolution using an insertion rate of from about 20 inches/min to about 60inches/min, preferably 40 inches/min, a dwell time of from about 0minute to about 5 seconds, preferably 0 seconds, and a withdrawal rateof from about 20 inches/minute to about 60 inches/minute, preferablyabout 40 inches/minute, and curing (drying) the domain from about 1minute to about 30 minutes, preferably from about 3 minutes to about 15minutes (and can be accomplished at room temperature or under vacuum(e.g., 20 to 30 mmHg)). In one exemplary embodiment including celluloseacetate butyrate interference domain, a 3-minute cure (i.e., dry) timeis preferred between each layer applied. In another exemplary embodimentemploying a cellulose acetate interference domain, a 15 minute cure(i.e., dry) time is preferred between each layer applied.

The dip process can be repeated at least one time and up to 10 times ormore. The preferred number of repeated dip processes depends upon thecellulosic derivative(s) used, their concentration, conditions duringdeposition (e.g., dipping) and the desired thickness (e.g., sufficientthickness to provide functional blocking of (or resistance to) certaininterferents), and the like. In some embodiments, 1 to 3 microns may bepreferred for the interference domain thickness; however, values outsideof these can be acceptable or even desirable in certain embodiments, forexample, depending upon viscosity and surface tension, as is appreciatedby one skilled in the art. In one exemplary embodiment, an interferencedomain is formed from three layers of cellulose acetate butyrate. Inanother exemplary embodiment, an interference domain is formed from 10layers of cellulose acetate. In alternative embodiments, theinterference domain can be formed using any known method and combinationof cellulose acetate and cellulose acetate butyrate, as will beappreciated by one skilled in the art.

In some embodiments, the electroactive surface can be cleaned prior toapplication of the interference domain 48. In some embodiments, theinterference domain 48 of the preferred embodiments can be useful as abioprotective or biocompatible domain, namely, a domain that interfaceswith host tissue when implanted in an animal (e.g., a human) due to itsstability and biocompatibility.

Enzyme Domain

In preferred embodiments, the membrane system further includes an enzymedomain 49 disposed more distally from the electroactive surfaces thanthe interference domain 48; however other configurations can bedesirable. In the preferred embodiments, the enzyme domain provides anenzyme to catalyze the reaction of the analyte and its co-reactant, asdescribed in more detail below. In the preferred embodiments of aglucose sensor, the enzyme domain includes glucose oxidase; howeverother oxidases, for example, galactose oxidase or uricase oxidase, canalso be used.

For an enzyme-based electrochemical glucose sensor to perform well, thesensor's response is preferably limited by neither enzyme activity norco-reactant concentration. Because enzymes, including glucose oxidase,are subject to deactivation as a function of time even in ambientconditions, this behavior is compensated for in forming the enzymedomain. Preferably, the enzyme domain is constructed of aqueousdispersions of colloidal polyurethane polymers including the enzyme.However, in alternative embodiments the enzyme domain is constructedfrom an oxygen enhancing material, for example, silicone, orfluorocarbon, in order to provide a supply of excess oxygen duringtransient ischemia. Preferably, the enzyme is immobilized within thedomain. See, e.g., U.S. patent application Ser. No. 10/896,639 filed onJul. 21, 2004 and entitled “Oxygen Enhancing Membrane Systems forImplantable Device.”

In preferred embodiments, the enzyme domain is deposited onto theinterference domain for a domain thickness of from about 0.05 micron orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3microns to about 3.5, 4, 4.5, or 5 microns. However in some embodiments,the enzyme domain can be deposited directly onto the electroactivesurfaces. Preferably, the enzyme domain is deposited by spray or dipcoating. In one embodiment of needle-type (transcutaneous) sensor suchas described herein, the enzyme domain is formed by dip coating theinterference domain coated sensor into an enzyme domain solution andcuring the domain for from about 15 to about 30 minutes at a temperatureof from about 40° C. to about 55° C. (and can be accomplished undervacuum (e.g., 20 to 30 mmHg)). In embodiments wherein dip coating isused to deposit the enzyme domain at room temperature, a preferredinsertion rate of from about 0.25 inch per minute to about 3 inches perminute, with a preferred dwell time of from about 0.5 minutes to about 2minutes, and a preferred withdrawal rate of from about 0.25 inch perminute to about 2 inches per minute provides a functional coating.However, values outside of those set forth above can be acceptable oreven desirable in certain embodiments, for example, depending uponviscosity and surface tension, as is appreciated by one skilled in theart. In one embodiment, the enzyme domain is formed by dip coating twotimes (namely, forming two layers) in an enzyme domain solution andcuring at 50° C. under vacuum for 20 minutes. However, in someembodiments, the enzyme domain can be formed by dip coating and/or spraycoating one or more layers at a predetermined concentration of thecoating solution, insertion rate, dwell time, withdrawal rate, and/ordesired thickness.

Resistance Domain

In preferred embodiments, the membrane system includes a resistancedomain 50 disposed more distal from the electroactive surfaces than theenzyme domain. Although the following description is directed to aresistance domain for a glucose sensor, the resistance domain can bemodified for other analytes and co-reactants as well.

There exists a molar excess of glucose relative to the amount of oxygenin blood; that is, for every free oxygen molecule in extracellularfluid, there are typically more than 100 glucose molecules present (seeUpdike et al., Diabetes Care 5:207-21(1982)). However, an immobilizedenzyme-based glucose sensor employing oxygen as co-reactant ispreferably supplied with oxygen in non-rate-limiting excess in order forthe sensor to respond linearly to changes in glucose concentration,while not responding to changes in oxygen concentration. Specifically,when a glucose-monitoring reaction is oxygen limited, linearity is notachieved above minimal concentrations of glucose. Without asemipermeable membrane situated over the enzyme domain to control theflux of glucose and oxygen, a linear response to glucose levels can beobtained only for glucose concentrations of up to about 40 mg/dL.However, in a clinical setting, a linear response to glucose levels isdesirable up to at least about 400 mg/dL.

The resistance domain includes a semipermeable membrane that controlsthe flux of oxygen and glucose to the underlying enzyme domain,preferably rendering oxygen in a non-rate-limiting excess. As a result,the upper limit of linearity of glucose measurement is extended to amuch higher value than that which is achieved without the resistancedomain. In one embodiment, the resistance domain exhibits an oxygen toglucose permeability ratio of from about 50:1 or less to about 400:1 ormore, preferably about 200:1. As a result, one-dimensional reactantdiffusion is adequate to provide excess oxygen at all reasonable glucoseand oxygen concentrations found in the subcutaneous matrix (See Rhodeset al., Anal. Chem., 66:1520-1529 (1994)).

In alternative embodiments, a lower ratio of oxygen-to-glucose can besufficient to provide excess oxygen by using a high oxygen solubilitydomain (for example, a silicone or fluorocarbon-based material ordomain) to enhance the supply/transport of oxygen to the enzyme domain.If more oxygen is supplied to the enzyme, then more glucose can also besupplied to the enzyme without creating an oxygen rate-limiting excess.In alternative embodiments, the resistance domain is formed from asilicone composition, such as is described in U.S. Publication No.US-2005-0090607-A1.

In a preferred embodiment, the resistance domain includes a polyurethanemembrane with both hydrophilic and hydrophobic regions to control thediffusion of glucose and oxygen to an analyte sensor, the membrane beingfabricated easily and reproducibly from commercially availablematerials. A suitable hydrophobic polymer component is a polyurethane,or polyetherurethaneurea. Polyurethane is a polymer produced by thecondensation reaction of a diisocyanate and a difunctionalhydroxyl-containing material. A polyurethaneurea is a polymer producedby the condensation reaction of a diisocyanate and a difunctionalamine-containing material. Preferred diisocyanates include aliphaticdiisocyanates containing from about 4 to about 8 methylene units.Diisocyanates containing cycloaliphatic moieties can also be useful inthe preparation of the polymer and copolymer components of the membranesof preferred embodiments. The material that forms the basis of thehydrophobic matrix of the resistance domain can be any of those known inthe art as appropriate for use as membranes in sensor devices and ashaving sufficient permeability to allow relevant compounds to passthrough it, for example, to allow an oxygen molecule to pass through themembrane from the sample under examination in order to reach the activeenzyme or electrochemical electrodes. Examples of materials which can beused to make non-polyurethane type membranes include vinyl polymers,polyethers, polyesters, polyamides, inorganic polymers such aspolysiloxanes and polycarbosiloxanes, natural polymers such ascellulosic and protein based materials, and mixtures or combinationsthereof.

In a preferred embodiment, the hydrophilic polymer component ispolyethylene oxide. For example, one useful hydrophobic-hydrophiliccopolymer component is a polyurethane polymer that includes about 20%hydrophilic polyethylene oxide. The polyethylene oxide portions of thecopolymer are thermodynamically driven to separate from the hydrophobicportions of the copolymer and the hydrophobic polymer component. The 20%polyethylene oxide-based soft segment portion of the copolymer used toform the final blend affects the water pick-up and subsequent glucosepermeability of the membrane.

In preferred embodiments, the resistance domain is deposited onto theenzyme domain to yield a domain thickness of from about 0.05 microns orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3microns to about 3.5, 4, 4.5, or 5 microns. Preferably, the resistancedomain is deposited onto the enzyme domain by vapor deposition, spraycoating, or dip coating. In one preferred embodiment, spray coating isthe preferred deposition technique. The spraying process atomizes andmists the solution, and therefore most or all of the solvent isevaporated prior to the coating material settling on the underlyingdomain, thereby minimizing contact of the solvent with the enzyme.

In another preferred embodiment, physical vapor deposition (e.g.,ultrasonic vapor deposition) is used for coating one or more of themembrane domain(s) onto the electrodes, wherein the vapor depositionapparatus and process include an ultrasonic nozzle that produces a mistof micro-droplets in a vacuum chamber. In these embodiments, themicro-droplets move turbulently within the vacuum chamber, isotropicallyimpacting and adhering to the surface of the substrate. Advantageously,vapor deposition as described above can be implemented to provide highproduction throughput of membrane deposition processes (e.g., at leastabout 20 to about 200 or more electrodes per chamber), greaterconsistency of the membrane on each sensor, and increased uniformity ofsensor performance, for example, as described below.

In some embodiments, depositing the resistance domain (for example, asdescribed in the preferred embodiments above) includes formation of amembrane system that substantially blocks or resists ascorbate (a knownelectrochemical interferant in hydrogen peroxide-measuring glucosesensors). While not wishing to be bound by theory, it is believed thatduring the process of depositing the resistance domain as described inthe preferred embodiments, a structural morphology is formed that ischaracterized in that ascorbate does not substantially permeatetherethrough.

In a preferred embodiment, the resistance domain is deposited on theenzyme domain by spray coating a solution of from about 1 wt. % to about5 wt. % polymer and from about 95 wt. % to about 99 wt. % solvent. Inspraying a solution of resistance domain material, including a solvent,onto the enzyme domain, it is desirable to mitigate or substantiallyreduce any contact with enzyme of any solvent in the spray solution thatcan deactivate the underlying enzyme of the enzyme domain.Tetrahydrofuran (THF) is one solvent that minimally or negligiblyaffects the enzyme of the enzyme domain upon spraying. Other solventscan also be suitable for use, as is appreciated by one skilled in theart.

Although a variety of spraying or deposition techniques can be used,spraying the resistance domain material and rotating the sensor at leastone time by 180° can typically provide adequate coverage by theresistance domain. Spraying the resistance domain material and rotatingthe sensor at least two times by 120° provides even greater coverage(one layer of 360° coverage), thereby ensuring resistivity to glucose,such as is described in more detail above.

In preferred embodiments, the resistance domain is spray coated andsubsequently cured for a time of from about 15 minutes to about 90minutes at a temperature of from about 40° C. to about 60° C. (and canbe accomplished under vacuum (e.g., from 20 to 30 mmHg)). A cure time ofup to about 90 minutes or more can be advantageous to ensure completedrying of the resistance domain.

In one embodiment, the resistance domain is formed by spray coating atleast six layers (namely, rotating the sensor seventeen times by 120°for at least six layers of 360° coverage) and curing at 50° C. undervacuum for 60 minutes. However, the resistance domain can be formed bydip coating or spray coating any layer or plurality of layers, dependingupon the concentration of the solution, insertion rate, dwell time,withdrawal rate, and/or the desired thickness of the resulting film.Additionally, curing in a convention oven can also be employed.

In certain embodiments, a variable frequency microwave oven can be usedto cure the membrane domains/layers. In general, microwave ovensdirectly excite the rotational mode of solvents. Consequently, microwaveovens cure coatings from the inside out rather than from the outside inas with conventional convection ovens. This direct rotational modeexcitation is responsible for the typically observed “fast” curingwithin a microwave oven. In contrast to conventional microwave ovens,which rely upon a fixed frequency of emission that can cause arcing ofdielectric (metallic) substrates if placed within a conventionalmicrowave oven, Variable Frequency Microwave (VFM) ovens emit thousandsof frequencies within 100 milliseconds, which substantially eliminatesarcing of dielectric substrates. Consequently, the membranedomains/layers can be cured even after deposition on metallic electrodesas described herein. While not wishing to be bound by theory, it isbelieve that VFM curing can increase the rate and completeness ofsolvent evaporation from a liquid membrane solution applied to a sensor,as compared to the rate and completeness of solvent evaporation observedfor curing in conventional convection ovens.

In certain embodiments, VFM is can be used together with convection ovencuring to further accelerate cure time. In some sensor applicationswherein the membrane is cured prior to application on the electrode(see, for example, U.S. Publication No. US-2005-0245799-A1, which isincorporated herein by reference in its entirety), conventionalmicrowave ovens (e.g., fixed frequency microwave ovens) can be used tocure the membrane layer.

Treatment of Interference Domain/Membrane System

Although the above-described methods generally include a curing step information of the membrane system, including the interference domain, thepreferred embodiments further include an additional treatment step,which can be performed directly after the formation of the interferencedomain and/or some time after the formation of the entire membranesystem (or anytime in between). In some embodiments, the additionaltreatment step is performed during (or in combination with)sterilization of the sensor.

In some embodiments, the membrane system (or interference domain) istreated by exposure to ionizing radiation, for example, electron beamradiation, UV radiation, X-ray radiation, gamma radiation, and the like.Alternatively, the membrane can be exposed to visible light whensuitable photoinitiators are incorporated into the interference domain.While not wishing to be bound by theory, it is believed that exposingthe interference domain to ionizing radiation substantially crosslinksthe interference domain and thereby creates a tighter, less permeablenetwork than an interference domain that has not been exposed toionizing radiation.

In some embodiments, the membrane system (or interference domain) iscrosslinked by forming free radicals, which may include the use ofionizing radiation, thermal initiators, chemical initiators,photoinitiators (e.g., UV and visible light), and the like. Any suitableinitiator or any suitable initiator system can be employed, for example,α-hydroxyketone, α-aminoketone, ammonium persulfate (APS), redox systemssuch as APS/bisulfite, or potassium permanganate. Suitable thermalinitiators include but are not limited to potassium persulfate, ammoniumpersulfate, sodium persulfate, and mixtures thereof.

In embodiments wherein electron beam radiation is used to treat themembrane system (or interference domain), a preferred exposure time isfrom about 6 k or 12 kGy to about 25 or 50 kGy, more preferably about 25kGy. However, one skilled in the art appreciates that choice ofmolecular weight, composition of cellulosic derivative (or otherpolymer), and/or the thickness of the layer can affect the preferredexposure time of membrane to radiation. Preferably, the exposure issufficient for substantially crosslinking the interference domain toform free radicals, but does not destroy or significantly break down themembrane or does not significantly damage the underlying electroactivesurfaces.

In embodiments wherein UV radiation is employed to treat the membrane,UV rays from about 200 nm to about 400 nm are preferred; however valuesoutside of this range can be employed in certain embodiments, dependentupon the cellulosic derivative and/or other polymer used.

In some embodiments, for example, wherein photoinitiators are employedto crosslink the interference domain, one or more additional domains canbe provided adjacent to the interference domain for preventingdelamination that may be caused by the crosslinking treatment. Theseadditional domains can be “tie layers” (i.e., film layers that enhanceadhesion of the interference domain to other domains of the membranesystem). In one exemplary embodiment, a membrane system is formed thatincludes the following domains: resistance domain, enzyme domain,electrode domain, and cellulosic-based interference domain, wherein theelectrode domain is configured to ensure adhesion between the enzymedomain and the interference domain. In embodiments whereinphotoinitiators are employed to crosslink the interference domain, UVradiation of greater than about 290 nm is preferred. Additionally, fromabout 0.01 to about 1 wt % photoinitiator is preferred weight-to-weightwith a preselected cellulosic polymer (e.g., cellulose acetate); howevervalues outside of this range can be desirable dependent upon thecellulosic polymer selected.

In general, sterilization of the transcutaneous sensor can be completedafter final assembly, utilizing methods such as electron beam radiation,gamma radiation, glutaraldehyde treatment, or the like. The sensor canbe sterilized prior to or after packaging. In an alternative embodiment,one or more sensors can be sterilized using variable frequency microwavechamber(s), which can increase the speed and reduce the cost of thesterilization process. In another alternative embodiment, one or moresensors can be sterilized using ethylene oxide (EtO) gas sterilization,for example, by treating with 100% ethylene oxide, which can be usedwhen the sensor electronics are not detachably connected to the sensorand/or when the sensor electronics must undergo a sterilization process.In one embodiment, one or more packaged sets of transcutaneous sensors(e.g., 1, 2, 3, 4, or 5 sensors or more) are sterilized simultaneously.

Signal Response

Advantageously, sensors with the membrane system of the preferredembodiments, including an electrode domain 47 and/or interference domain48, an enzyme domain 49, and a resistance domain 50, provide stablesignal response to increasing glucose levels of from about 40 to about400 mg/dL, and sustained function (at least 90% signal strength) even atlow oxygen levels (for example, at about 0.6 mg/L O₂). While not wishingto be bound by theory, it is believed that the resistance domainprovides sufficient resistivity, or the enzyme domain providessufficient enzyme, such that oxygen limitations are seen at a much lowerconcentration of oxygen as compared to prior art sensors.

In preferred embodiments, a sensor signal with a current in the picoAmprange is preferred, which is described in more detail elsewhere herein.However, the ability to produce a signal with a current in the picoAmprange can be dependent upon a combination of factors, including theelectronic circuitry design (e.g., A/D converter, bit resolution, andthe like), the membrane system (e.g., permeability of the analytethrough the resistance domain, enzyme concentration, and/or electrolyteavailability to the electrochemical reaction at the electrodes), and theexposed surface area of the working electrode. For example, theresistance domain can be designed to be more or less restrictive to theanalyte depending upon to the design of the electronic circuitry,membrane system, and/or exposed electroactive surface area of theworking electrode.

Accordingly, in preferred embodiments, the membrane system is designedwith a sensitivity of from about 1 pA/mg/dL to about 100 pA/mg/dL,preferably from about 5 pA/mg/dL to 25 pA/mg/dL, and more preferablyfrom about 3.5 to about 7.5 pA/mg/dL. While not wishing to be bound byany particular theory, it is believed that membrane systems designedwith a sensitivity in the preferred ranges permit measurement of theanalyte signal in low analyte and/or low oxygen situations. Namely,conventional analyte sensors have shown reduced measurement accuracy inlow analyte ranges due to lower availability of the analyte to thesensor and/or have shown increased signal noise in high analyte rangesdue to insufficient oxygen necessary to react with the amount of analytebeing measured. While not wishing to be bound by theory, it is believedthat the membrane systems of the preferred embodiments, in combinationwith the electronic circuitry design and exposed electrochemicalreactive surface area design, support measurement of the analyte in thepicoAmp range, which enables an improved level of resolution andaccuracy in both low and high analyte ranges not seen in the prior art.

Mutarotase Enzyme

In some embodiments, mutarotase, an enzyme that converts α D-glucose toβ D-glucose, is incorporated into the membrane system. Mutarotase can beincorporated into the enzyme domain and/or can be incorporated intoanother domain of the membrane system. In general, glucose exists in twodistinct isomers, α and β, which are in equilibrium with one another insolution and in the blood or interstitial fluid. At equilibrium, α ispresent at a relative concentration of about 35.5% and β is present inthe relative concentration of about 64.5% (see Okuda et. al., AnalBiochem. 1971 September; 43(1):312-5). Glucose oxidase, which is aconventional enzyme used to react with glucose in glucose sensors,reacts with β D-glucose and not with α D-glucose. Since only the βD-glucose isomer reacts with the glucose oxidase, errant readings mayoccur in a glucose sensor responsive to a shift of the equilibriumbetween the α D-glucose and the β D-glucose. Many compounds, such ascalcium, can affect equilibrium shifts of α D-glucose and β D-glucose.For example, as disclosed in U.S. Pat. No. 3,964,974 to Banaugh et al.,compounds that exert a mutarotation accelerating effect on α D-glucoseinclude histidine, aspartic acid, imidazole, glutamic acid, α hydroxylpyridine, and phosphate.

Accordingly, a shift in α D-glucose and β D-glucose equilibrium cancause a glucose sensor based on glucose oxidase to err high or low. Toovercome the risks associated with errantly high or low sensor readingsdue to equilibrium shifts, the sensor of the preferred embodiments canbe configured to measure total glucose in the host, including αD-glucose and β D-glucose by the incorporation of the mutarotase enzyme,which converts α D-glucose to β D-glucose.

Although sensors of some embodiments described herein include aninterference domain in order to block or reduce one or moreinterferents, sensors with the membrane systems of the preferredembodiments, including an electrode domain 47, an enzyme domain 48, anda resistance domain 49, have been shown to inhibit ascorbate without anadditional interference domain. Namely, the membrane system of thepreferred embodiments, including an electrode domain 47, an enzymedomain 48, and a resistance domain 49, has been shown to besubstantially non-responsive to ascorbate in physiologically acceptableranges. While not wishing to be bound by theory, it is believed that theprocessing process of spraying the depositing the resistance domain byspray coating, as described herein, forms results in a structuralmorphology that is substantially resistance resistant to ascorbate.

Oxygen Conduit

As described above, certain sensors depend upon an enzyme within themembrane system through which the host's bodily fluid passes and inwhich the analyte (for example, glucose) within the bodily fluid reactsin the presence of a co-reactant (for example, oxygen) to generate aproduct. The product is then measured using electrochemical methods, andthus the output of an electrode system functions as a measure of theanalyte. For example, when the sensor is a glucose oxidase based glucosesensor, the species measured at the working electrode is H₂O₂. Anenzyme, glucose oxidase, catalyzes the conversion of oxygen and glucoseto hydrogen peroxide and gluconate according to the following reaction:Glucose+O₂→Gluconate+H₂O₂

Because for each glucose molecule reacted there is a proportional changein the product, H₂O₂, one can monitor the change in H₂O₂ to determineglucose concentration. Oxidation of H₂O₂ by the working electrode isbalanced by reduction of ambient oxygen, enzyme generated H₂O₂ and otherreducible species at a counter electrode, for example. See Fraser, D.M., “An Introduction to In vivo Biosensing: Progress and Problems.” In“Biosensors and the Body,” D. M. Fraser, ed., 1997, pp. 1-56 John Wileyand Sons, New York))

In vivo, glucose concentration is generally about one hundred times ormore that of the oxygen concentration. Consequently, oxygen is alimiting reactant in the electrochemical reaction, and when insufficientoxygen is provided to the sensor, the sensor is unable to accuratelymeasure glucose concentration. Thus, depressed sensor function orinaccuracy is believed to be a result of problems in availability ofoxygen to the enzyme and/or electroactive surface(s).

Accordingly, in an alternative embodiment, an oxygen conduit (forexample, a high oxygen solubility domain formed from silicone orfluorochemicals) is provided that extends from the ex vivo portion ofthe sensor to the in vivo portion of the sensor to increase oxygenavailability to the enzyme. The oxygen conduit can be formed as a partof the coating (insulating) material or can be a separate conduitassociated with the assembly of wires that forms the sensor.

Porous Biointerface Materials

In alternative embodiments, the distal portion 42 includes a porousmaterial disposed over some portion thereof, which modifies the host'stissue response to the sensor. In some embodiments, the porous materialsurrounding the sensor advantageously enhances and extends sensorperformance and lifetime in the short term by slowing or reducingcellular migration to the sensor and associated degradation that wouldotherwise be caused by cellular invasion if the sensor were directlyexposed to the in vivo environment. Alternatively, the porous materialcan provide stabilization of the sensor via tissue ingrowth into theporous material in the long term. Suitable porous materials includesilicone, polytetrafluoroethylene, expanded polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polyvinylalcohol (PVA), polybutylene terephthalate (PBT), polymethylmethacrylate(PMMA), polyether ether ketone (PEEK), polyamides, polyurethanes,cellulosic polymers, polysulfones and block copolymers thereofincluding, for example, di-block, tri-block, alternating, random andgraft copolymers, as well as metals, ceramics, cellulose, hydrogelpolymers, poly(2-hydroxyethyl methacrylate, pHEMA), hydroxyethylmethacrylate, (HEMA), polyacrylonitrile-polyvinyl chloride (PAN-PVC),high density polyethylene, acrylic copolymers, nylon, polyvinyldifluoride, polyanhydrides, poly(l-lysine), poly(L-lactic acid),hydroxyethylmethacrylate, hydroxyapeptite, alumina, zirconia, carbonfiber, aluminum, calcium phosphate, titanium, titanium alloy, nintinol,stainless steel, and CoCr alloy, or the like, such as are described inU.S. Publication No. US-2005-0031689-A1 and U.S. Publication No.US-2005-0112169-A1.

In some embodiments, the porous material surrounding the sensor providesunique advantages in the short term (e.g., one to 30 days) that can beused to enhance and extend sensor performance and lifetime. However,such materials can also provide advantages in the long term too (e.g.,greater than 30 days). Particularly, the in vivo portion of the sensor(the portion of the sensor that is implanted into the host's tissue) isencased (partially or fully) in a porous material. The porous materialcan be wrapped around the sensor (for example, by wrapping the porousmaterial around the sensor or by inserting the sensor into a section ofporous material sized to receive the sensor). Alternately, the porousmaterial can be deposited on the sensor (for example, by electrospinningof a polymer directly thereon). In yet other alternative embodiments,the sensor is inserted into a selected section of porous biomaterial.Other methods for surrounding the in vivo portion of the sensor with aporous material can also be used as is appreciated by one skilled in theart.

The porous material surrounding the sensor advantageously slows orreduces cellular migration to the sensor and associated degradation thatwould otherwise be caused by cellular invasion if the sensor weredirectly exposed to the in vivo environment. Namely, the porous materialprovides a barrier that makes the migration of cells towards the sensormore tortuous and therefore slower (providing short term advantages). Itis believed that this reduces or slows the sensitivity loss normallyobserved in a short-term sensor over time.

In an embodiment wherein the porous material is a high oxygen solubilitymaterial, such as porous silicone, the high oxygen solubility porousmaterial surrounds some of or the entire in vivo portion 42 of thesensor. High oxygen solubility materials are materials that dynamicallyretain a high availability of oxygen that can be used to compensate forthe local oxygen deficit during times of transient ischemia (e.g.,silicone and fluorocarbons). It is believed that some signal noisenormally seen by a conventional sensor can be attributed to an oxygendeficit. In one exemplary embodiment, porous silicone surrounds thesensor and thereby effectively increases the concentration of oxygenlocal (proximal) to the sensor. Thus, an increase in oxygen availabilityproximal to the sensor as achieved by this embodiment ensures that anexcess of oxygen over glucose is provided to the sensor; therebyreducing the likelihood of oxygen limited reactions therein.Accordingly, by providing a high oxygen solubility material (e.g.,porous silicone) surrounding the in vivo portion of the sensor, it isbelieved that increased oxygen availability, reduced signal noise,longevity, and ultimately enhanced sensor performance can be achieved.

Bioactive Agents

In some alternative embodiments, a bioactive agent is incorporated intothe above described porous material and/or membrane system, whichdiffuses out into the environment adjacent to the sensing region, suchas is described in U.S. Publication No. US-2005-0031689-A1. Additionallyor alternately, a bioactive agent can be administered locally at theexit-site or implantation-site. Suitable bioactive agents are those thatmodify the host's tissue response to the sensor, for exampleanti-inflammatory agents, anti-infective agents, anesthetics,inflammatory agents, growth factors, immunosuppressive agents,antiplatelet agents, anti-coagulants, anti-proliferates, ACE inhibitors,cytotoxic agents, anti-barrier cell compounds, vascularization-inducingcompounds, anti-sense molecules, or mixtures thereof, such as aredescribed in more detail in co-pending U.S. Patent Publication No.US-2005-0031689-A1.

In embodiments wherein the porous material is designed to enhanceshort-term (e.g., from about 1 to about 30 days) lifetime or performanceof the sensor, a suitable bioactive agent can be chosen to ensure thattissue ingrowth does not substantially occur within the pores of theporous material. Namely, by providing a tissue modifying bioactiveagent, such as an anti-inflammatory agent (for example, Dexamethasone),substantially tissue ingrowth can be inhibited, at least in the shortterm, in order to maintain sufficient glucose transport through thepores of the porous material to maintain a stable sensitivity.

In embodiments wherein the porous material is designed to enhancelong-term (e.g., from about a day to about a year or more) lifetime orperformance of the sensor, a suitable bioactive agent, such as avascularization-inducing compound or anti-barrier cell compound, can bechosen to encourage tissue ingrowth without barrier cell formation.

In some alternative embodiments, the in vivo portion of the sensor isdesigned with porosity therethrough, for example, a design wherein thesensor wires are configured in a mesh, loose helix configuration(namely, with spaces between the wires), or with micro-fabricated holestherethrough. Porosity within the sensor modifies the host's tissueresponse to the sensor, because tissue ingrowth into and/or through thein vivo portion of the sensor increases stability of the sensor and/orimproves host acceptance of the sensor, thereby extending the lifetimeof the sensor in vivo.

Sensor Manufacture

In some embodiments, the sensor is manufactured partially or whollyusing a continuous reel-to-reel process, wherein one or moremanufacturing steps are automated. In such embodiments, a manufacturingprocess can be provided substantially without the need for manualmounting and fixing steps and substantially without the need humaninteraction. A process can be utilized wherein a plurality of sensors ofthe preferred embodiments, including the electrodes, insulator, andmembrane system, are continuously manufactured in a semi-automated orautomated process.

In one embodiment, a plurality of twisted pairs is continuously formedinto a coil, wherein a working electrode is coated with an insulatormaterial around which a plurality of reference electrodes is wound. Theplurality of twisted pairs are preferably indexed and subsequently movedfrom one station to the next whereby the membrane system is seriallydeposited according to the preferred embodiments. Preferably, the coilis continuous and remains as such during the entire sensor fabricationprocess, including winding of the electrodes, insulator application, andmembrane coating processes. After drying of the membrane system, eachindividual sensor is cut from the continuous coil.

A continuous reel-to-reel process for manufacturing the sensoreliminates possible sensor damage due to handling by eliminatinghandling steps, and provides faster manufacturing due to faster troubleshooting by isolation when a product fails. Additionally, a process runcan be facilitated because of elimination of steps that would otherwisebe required (e.g., steps in a manual manufacturing process). Finally,increased or improved product consistency due to consistent processeswithin a controlled environment can be achieved in a machine or robotdriven operation.

In certain embodiments, vapor deposition (e.g., physical vapordeposition) is utilized to deposit one or more of the membrane domainsonto the sensor. Vapor deposition can be used to coat one or moreinsulating layers onto the electrodes and one or more of the domains ofthe membrane system onto the electrochemically reactive surfaces. Thevapor deposition process can be a part of a continuous manufacturingprocess, for example, a semi-automated or fully-automated manufacturingprocess. Physical vapor deposition processes are generally preferred. Insuch physical vapor deposition processes in the gas phase for forming athin film, source material is physically transferred in a vacuum to thesubstrate without any chemical reaction(s) involved. Physical vapordeposition processes include evaporation (e.g., by thermal or e-beam)and sputtering processes. In alternative embodiments, chemical vapordeposition can be used. In chemical vapor deposition processes fordepositing a thin film, the substrate is exposed to one or more volatileprecursors, which react and/or decompose on the substrate surface toproduce the desired deposit. Advantageously, vapor deposition processescan be implemented to provide high production throughput of membranedeposition processes (e.g., deposition on at least about 20 to about 200or more electrodes per chamber), greater consistency of the membrane oneach sensor, and increased uniformity of sensor performance, asdescribed below.

Applicator

FIG. 6 is an exploded side view of an applicator, showing the componentsthat enable sensor and needle insertion. In this embodiment, theapplicator 12 includes an applicator body 18 that aides in aligning andguiding the applicator components. Preferably, the applicator body 18includes an applicator body base 60 that matingly engages the mountingunit 14 and an applicator body cap 62 that enables appropriaterelationships (for example, stops) between the applicator components.

The guide tube subassembly 20 includes a guide tube carrier 64 and aguide tube 66. In some embodiments, the guide tube is a cannula. Theguide tube carrier 64 slides along the applicator body 18 and maintainsthe appropriate relative position of the guide tube 66 during insertionand subsequent retraction. For example, prior to and during insertion ofthe sensor, the guide tube 66 extends through the contact subassembly 26to maintain an opening that enables easy insertion of the needletherethrough (see FIGS. 7A to 7D). During retraction of the sensor, theguide tube subassembly 20 is pulled back, engaging with and causing theneedle and associated moving components to retract back into theapplicator 12 (See FIGS. 7C and 7D). In some embodiments, a lubricant(e.g., petroleum jelly) is placed within the sealing member 36 of thecontact subassembly such that it surrounds the guide tube (e.g.,cannula), thereby allowing the guide tube to easily retract back intothe applicator, for example, without causing compression or deformationof the sealing member 36.

A needle subassembly 68 is provided that includes a needle carrier 70and needle 72. The needle carrier 70 cooperates with the otherapplicator components and carries the needle 72 between its extended andretracted positions. The needle can be of any appropriate size that canencompass the sensor 32 and aid in its insertion into the host.Preferred sizes include from about 32 gauge or less to about 18 gauge ormore, more preferably from about 28 gauge to about 25 gauge, to providea comfortable insertion for the host. Referring to the inner diameter ofthe needle, approximately 0.006 inches to approximately 0.023 inches ispreferable, and 0.013 inches is most preferable. The needle carrier 70is configured to engage with the guide tube carrier 64, while the needle72 is configured to slidably nest within the guide tube 66, which allowsfor easy guided insertion (and retraction) of the needle through thecontact subassembly 26.

A push rod subassembly 74 is provided that includes a push rod carrier76 and a push rod 78. The push rod carrier 76 cooperates with otherapplicator components to ensure that the sensor is properly insertedinto the host's skin, namely the push rod carrier 76 carries the pushrod 78 between its extended and retracted positions. In this embodiment,the push rod 78 is configured to slidably nest within the needle 72,which allows for the sensor 32 to be pushed (released) from the needle72 upon retraction of the needle, which is described in more detail withreference to FIGS. 7A through 7D. In some embodiments, a slight bend orserpentine shape is designed into or allowed in the sensor in order tomaintain the sensor within the needle by interference. While not wishingto be bound by theory, it is believed that a slight friction fit of thesensor within the needle minimizes motion of the sensor duringwithdrawal of the needle and maintains the sensor within the needleprior to withdrawal of the needle.

A plunger subassembly 22 is provided that includes a plunger 80 andplunger cap 82. The plunger subassembly 22 cooperates with otherapplicators components to ensure proper insertion and subsequentretraction of the applicator components. In this embodiment, the plunger80 is configured to engage with the push rod to ensure the sensorremains extended (namely, in the host) during retraction, such as isdescribed in more detail with reference to FIG. 7C.

Sensor Insertion

FIGS. 7A through 7D are schematic side cross-sectional views thatillustrate the applicator components and their cooperating relationshipsat various stages of sensor insertion. FIG. 7A illustrates the needleand sensor loaded prior to sensor insertion. FIG. 7B illustrates theneedle and sensor after sensor insertion. FIG. 7C illustrates the sensorand needle during needle retraction. FIG. 7D illustrates the sensorremaining within the contact subassembly after needle retraction.Although the embodiments described herein suggest manual insertionand/or retraction of the various components, automation of one or moreof the stages can also be employed. For example, spring-loadedmechanisms that can be triggered to automatically insert and/or retractthe sensor, needle, or other cooperative applicator components can beimplemented.

Referring to FIG. 7A, the sensor 32 is shown disposed within the needle72, which is disposed within the guide tube 66. In this embodiment, theguide tube 66 is provided to maintain an opening within the contactsubassembly 26 and/or contacts 28 to provide minimal friction betweenthe needle 72 and the contact subassembly 26 and/or contacts 28 duringinsertion and retraction of the needle 72. However, the guide tube is anoptional component, which can be advantageous in some embodimentswherein the contact subassembly 26 and/or the contacts 28 are formedfrom an elastomer or other material with a relatively high frictioncoefficient, and which can be omitted in other embodiments wherein thecontact subassembly 26 and or the contacts 28 are formed from a materialwith a relatively low friction coefficient (for example, hard plastic ormetal). A guide tube, or the like, can be preferred in embodimentswherein the contact subassembly 26 and/or the contacts 28 are formedfrom a material designed to frictionally hold the sensor 32 (see FIG.7D), for example, by the relaxing characteristics of an elastomer, orthe like. In these embodiments, the guide tube is provided to easeinsertion of the needle through the contacts, while allowing for africtional hold of the contacts on the sensor 32 upon subsequent needleretraction. Stabilization of the sensor in or on the contacts 28 isdescribed in more detail with reference to FIG. 7D and following.Although FIG. 7A illustrates the needle and sensor inserted into thecontacts subassembly as the initial loaded configuration, alternativeembodiments contemplate a step of loading the needle through the guidetube 66 and/or contacts 28 prior to sensor insertion.

Referring to FIG. 7B, the sensor 32 and needle 72 are shown in anextended position. In this stage, the pushrod 78 has been forced to aforward position, for example by pushing on the plunger shown in FIG. 6,or the like. The plunger 22 (FIG. 6) is designed to cooperate with otherof the applicator components to ensure that sensor 32 and the needle 72extend together to a forward position (as shown); namely, the push rod78 is designed to cooperate with other of the applicator components toensure that the sensor 32 maintains the forward position simultaneouslywithin the needle 72.

Referring to FIG. 7C, the needle 72 is shown during the retractionprocess. In this stage, the push rod 78 is held in its extended(forward) position in order to maintain the sensor 32 in its extended(forward) position until the needle 72 has substantially fully retractedfrom the contacts 28. Simultaneously, the cooperating applicatorcomponents retract the needle 72 and guide tube 66 backward by a pullingmotion (manual or automated) thereon. In preferred embodiments, theguide tube carrier 64 (FIG. 6) engages with cooperating applicatorcomponents such that a backward (retraction) motion applied to the guidetube carrier retracts the needle 72 and guide tube 66, without(initially) retracting the push rod 78. In an alternative embodiment,the push rod 78 can be omitted and the sensor 32 held it its forwardposition by a cam, elastomer, or the like, which is in contact with aportion of the sensor while the needle moves over another portion of thesensor. One or more slots can be cut in the needle to maintain contactwith the sensor during needle retraction.

Referring to FIG. 7D, the needle 72, guide tube 66, and push rod 78 areall retracted from contact subassembly 26, leaving the sensor 32disposed therein. The cooperating applicator components are designedsuch that when the needle 72 has substantially cleared from the contacts28 and/or contact subassembly 26, the push rod 78 is retracted alongwith the needle 72 and guide tube 66. The applicator 12 can then bereleased (manually or automatically) from the contacts 28, such as isdescribed in more detail elsewhere herein, for example with reference toFIGS. 8D and 9A.

The preferred embodiments are generally designed with elastomericcontacts to ensure a retention force that retains the sensor 32 withinthe mounting unit 14 and to ensure stable electrical connection of thesensor 32 and its associated contacts 28. Although the illustratedembodiments and associated text describe the sensor 32 extending throughthe contacts 28 to form a friction fit therein, a variety ofalternatives are contemplated. In one alternative embodiment, the sensoris configured to be disposed adjacent to the contacts (rather thanbetween the contacts). The contacts can be constructed in a variety ofknown configurations, for example, metallic contacts, cantileveredfingers, pogo pins, or the like, which are configured to press againstthe sensor after needle retraction.

It is generally preferred that a contact 28 is formed from a materialwith a durometer hardness of from about 5 to about 80 Shore A, morepreferably from about 10 to about 50 Shore A, and even more preferablyfrom about 20 to about 50 Shore A. In one implementation of atranscutaneous analyte sensor as described with reference to thepreferred embodiments, the contact 28 is formed from a material with adurometer hardness of about 20 Shore A to maximize conformance (e.g.,compression) of the contact around the sensor and/or within the sealingmember. In another implementation of a transcutaneous analyte sensor asdescribed with reference to the preferred embodiments, the contact 28 isformed from a material with a durometer hardness of about 50 Shore A toincrease the strength of the contact 28 (e.g., increase resistance tocompression). While a few examples have been provided above, one skilledin the art will appreciate that higher or lower durometer hardnesssealing materials can also be advantageously employed.

In some embodiments, the durometer hardness of the elastomeric contacts28 is higher than the durometer hardness of the sealing member 36. Inone example, the durometer hardness of the contacts is about 50 Shore Aand the durometer hardness of the sealing member is about 20 Shore A;however, a variety of durometer hardness materials within the preferredrange (typically, from about 5 Shore A to about 80 Shore A) can bechosen. In these embodiments, the higher durometer hardness contactsgenerally provide greater stability while the lower durometer hardnesssealing member generally provides superior compression and/or sealaround the contacts.

In some embodiments, the durometer hardness of the sealing member 36 ishigher than the durometer hardness of the elastomeric contacts 28. Inone example, the durometer hardness of the sealing member is about 50Shore A and the durometer hardness of the contacts is about 20 Shore A,however a variety of durometer hardness materials within the preferredrange (typically, from about 5 Shore A to about 80 Shore A) can bechosen. In these embodiments, the higher durometer hardness sealingmember provides greater stability while the lower durometer hardnesscontacts provide superior compression and/or seal.

The illustrated embodiments are designed with coaxial contacts 28;namely, the contacts 28 are configured to contact the working andreference electrodes 44, 46 axially along the distal portion 42 of thesensor 32 (see FIG. 5A). As shown in FIG. 5A, the working electrode 44extends farther than the reference electrode 46, which allows coaxialconnection of the electrodes 44, 46 with the contacts 28 at locationsspaced along the distal portion of the sensor (see also FIGS. 9B and10B). Although the illustrated embodiments employ a coaxial design,other designs are contemplated within the scope of the preferredembodiments. For example, the reference electrode can be positionedsubstantially adjacent to (but spaced apart from) the working electrodeat the distal portion of the sensor. In this way, the contacts 28 can bedesigned side-by-side rather than co-axially along the axis of thesensor.

FIG. 8A is a perspective view of an applicator and mounting unit in oneembodiment including a safety latch mechanism 84. The safety latchmechanism 84 is configured to lock the plunger subassembly 22 in astationary position such that it cannot be accidentally pushed prior torelease of the safety latch mechanism. In this embodiment, the sensorsystem 10 is preferably packaged (e.g., shipped) in this lockedconfiguration, wherein the safety latch mechanism 84 holds the plungersubassembly 22 in its extended position, such that the sensor 32 cannotbe prematurely inserted (e.g., accidentally released). The safety latchmechanism 84 is configured such that a pulling force shown in thedirection of the arrow (see FIG. 8A) releases the lock of the safetylatch mechanism on the plunger subassembly, thereby allowing sensorinsertion. Although one safety latch mechanism that locks the plungersubassembly is illustrated and described herein, a variety of safetylatch mechanism configurations that lock the sensor to prevent it fromprematurely releasing (i.e., that lock the sensor prior to release ofthe safety latch mechanism) are contemplated, as can be appreciated byone skilled in the art, and fall within the scope of the preferredembodiments.

FIG. 8A additionally illustrates a force-locking mechanism 86 includedin certain alternative embodiments of the sensor system, wherein theforce-locking mechanism 86 is configured to ensure a proper mate betweenthe electronics unit 16 and the mounting unit 14 (see FIG. 12A, forexample). In embodiments wherein a seal is formed between the mountingunit and the electronics unit, as described in more detail elsewhereherein, an appropriate force may be required to ensure a seal hassufficiently formed therebetween; in some circumstances, it can beadvantageous to ensure the electronics unit has been properly mated(e.g., snap-fit or sealingly mated) to the mounting unit. Accordingly,upon release of the applicator 12 from the mounting unit 14 (aftersensor insertion), and after insertion of the electronics unit 16 intothe mounting unit 14, the force-locking mechanism 86 allows the user toensure a proper mate and/or seal therebetween. In practice, a userpivots (e.g., lifts or twists) the force-locking mechanism such that itprovides force on the electronics unit 16 by pulling up on the circulartab illustrated in FIG. 8A; the force-locking mechanism is preferablyreleased thereafter. Although one system and one method for providing asecure and/or sealing fit between the electronics unit and the mountingunit are illustrated, various other force-locking mechanisms can beemployed that utilize a variety of systems and methods for providing asecure and/or sealing fit between the electronics unit and the mountingunit (housing).

FIGS. 8B to 8D are side views of an applicator and mounting unit in oneembodiment, showing various stages of sensor insertion. FIG. 8B is aside view of the applicator matingly engaged to the mounting unit priorto sensor insertion. FIG. 8C is a side view of the mounting unit andapplicator after the plunger subassembly has been pushed, extending theneedle and sensor from the mounting unit (namely, through the host'sskin). FIG. 8D is a side view of the mounting unit and applicator afterthe guide tube subassembly has been retracted, retracting the needleback into the applicator. Although the drawings and associated textillustrate and describe embodiments wherein the applicator is designedfor manual insertion and/or retraction, automated insertion and/orretraction of the sensor/needle, for example, using spring-loadedcomponents, can alternatively be employed.

The preferred embodiments advantageously provide a system and method foreasy insertion of the sensor and subsequent retraction of the needle ina single push-pull motion. Because of the mechanical latching system ofthe applicator, the user provides a continuous force on the plunger cap82 and guide tube carrier 64 that inserts and retracts the needle in acontinuous motion. When a user grips the applicator, his or her fingersgrasp the guide tube carrier 64 while his or her thumb (or anotherfinger) is positioned on the plunger cap 82. The user squeezes his orher fingers and thumb together continuously, which causes the needle toinsert (as the plunger slides forward) and subsequently retract (as theguide tube carrier slides backward) due to the system of latches locatedwithin the applicator (FIGS. 6 to 8) without any necessary change ofgrip or force, leaving the sensor implanted in the host. In someembodiments, a continuous torque, when the applicator components areconfigured to rotatingly engage one another, can replace the continuousforce. Some prior art sensors, in contrast to the sensors of thepreferred embodiments, suffer from complex, multi-step, ormulti-component insertion and retraction steps to insert and remove theneedle from the sensor system.

FIG. 8B shows the mounting unit and applicator in the ready position.The sensor system can be shipped in this configuration, or the user canbe instructed to mate the applicator 12 with the mounting unit 14 priorto sensor insertion. The insertion angle α is preferably fixed by themating engagement of the applicator 12. In the illustrated embodiment,the insertion angle α is fixed in the applicator 12 by the angle of theapplicator body base 60 with the shaft of the applicator body 18.However, a variety of systems and methods of ensuring proper placementcan be implemented. Proper placement ensures that at least a portion ofthe sensor 32 extends below the dermis of the host upon insertion. Inalternative embodiments, the sensor system 10 is designed with a varietyof adjustable insertion angles. A variety of insertion angles can beadvantageous to accommodate a variety of insertion locations and/orindividual dermis configurations (for example, thickness of the dermis).In preferred embodiments, the insertion angle α is from about 0 to about90 degrees, more preferably from about 30 to about 60 degrees, and evenmore preferably about 45 degrees.

In practice, the mounting unit is placed at an appropriate location onthe host's skin, for example, the skin of the arm, thigh, or abdomen.Thus, removing the backing layer 9 from the adhesive pad 8 and pressingthe base portion of the mounting unit on the skin adheres the mountingunit to the host's skin.

FIG. 8C shows the mounting unit and applicator after the needle 72 hasbeen extended from the mounting unit 14 (namely, inserted into the host)by pushing the push rod subassembly 22 into the applicator 12. In thisposition, the sensor 32 is disposed within the needle 72 (namely, inposition within the host), and held by the cooperating applicatorcomponents. In alternative embodiments, the mounting unit and/orapplicator can be configured with the needle/sensor initially extended.In this way, the mechanical design can be simplified and theplunger-assisted insertion step can be eliminated or modified. Theneedle can be simply inserted by a manual force to puncture the host'sskin, and only one (pulling) step is required on the applicator, whichremoves the needle from the host's skin.

FIG. 8D shows the mounting unit and applicator after the needle 72 hasbeen retracted into the applicator 12, exposing the sensor 32 to thehost's tissue. During needle retraction, the push rod subassemblymaintains the sensor in its extended position (namely, within the host).In preferred embodiments, retraction of the needle irreversibly locksthe needle within the applicator so that it cannot be accidentallyand/or intentionally released, reinserted, or reused. The applicator ispreferably configured as a disposable device to reduce or eliminate apossibility of exposure of the needle after insertion into the host.However a reusable or reloadable applicator is also contemplated in somealternative embodiments. After needle retraction, the applicator 12 canbe released from the mounting unit, for example, by pressing the releaselatch(es) 30, and the applicator disposed of appropriately. Inalternative embodiments, other mating and release configurations can beimplemented between the mounting unit and the applicator, or theapplicator can automatically release from the mounting unit after sensorinsertion and subsequent needle retraction. In one alternativeembodiment, a retention hold (e.g., ball and detent configuration) holdsand releases the electronics unit (or applicator).

In one alternative embodiment, the mounting unit is configured toreleasably mate with the applicator and electronics unit in a mannersuch that when the applicator is releasably mated to the mounting unit(e.g., after sensor insertion), the electronics unit is configured toslide into the mounting unit, thereby triggering release of theapplicator and simultaneous mating of the electronics unit to themounting unit. Cooperating mechanical components, for example, slidingball and detent type configurations, can be used to accomplish thesimultaneous mating of electronics unit and release of the applicator.

FIGS. 8E to 8G are perspective views of a sensor system 310 of analternative embodiment, including an applicator 312, electronics unit316, and mounting unit 314, showing various stages of applicator releaseand/or electronic unit mating. FIG. 8E is a perspective view of theapplicator matingly engaged to the mounting unit after sensor insertion.FIG. 8F is a perspective view of the mounting unit and applicatormatingly engaged while the electronics unit is slidingly inserted intothe mounting unit. FIG. 8G is a perspective view of the electronics unitmatingly engaged with the mounting unit after the applicator has beenreleased.

In general, the sensor system 310 comprises a sensor adapted fortranscutaneous insertion into a host's skin; a housing 314 adapted forplacement adjacent to the host's skin; an electronics unit 316releasably attachable to the housing; and an applicator 312 configuredto insert the sensor through the housing 314 and into the skin of thehost, wherein the applicator 312 is adapted to releasably mate with thehousing 314, and wherein the system 310 is configured to release theapplicator 312 from the housing when the electronics unit 316 isattached to the housing 314.

FIG. 8E shows the sensor system 310 after the sensor has been insertedand prior to release of the applicator 312. In this embodiment, theelectronics unit 316 is designed to slide into the mounting unit 314.Preferably, the electronics unit 316 is configured and arranged to slideinto the mounting unit 314 in only one orientation. In the illustratedembodiment, the insertion end is slightly tapered and dovetailed inorder to guide insertion of the electronics unit 316 into the housing314; however other self-alignment configurations are possible. In thisway, the electronics unit 316 self-aligns and orients the electronicsunit 316 in the housing, ensuring a proper fit and a secure electronicconnection with the sensor.

FIG. 8F shows the sensor system 310 after the electronics unit 316 hasbeen inserted therein. Preferably, the electronic unit 316 slide-fitsinto the mounting unit. In some embodiments, the sensor system 310 canbe designed to allow the electronics unit 316 to be attached to themounting unit 314 (i.e., operably connected to the sensor) before thesensor system 310 is affixed to the host. Advantageously, this designprovides mechanical stability for the sensor during transmitterinsertion.

FIG. 8G shows the sensor system 310 upon release of the applicator 312from the mounting unit 314 and electronics unit 316. In this embodiment,the sensor system 310 is configured such that mating the electronicsunit to the mounting unit triggers the release of the applicator 312from the mounting unit 314.

Thus, the above described sensor system 310, also referred to as theslide-in system, allows for self-alignment of the electronics unit,creates an improved seal around the contacts due to greater holdingforce, provides mechanical stability for the sensor during insertion ofthe electronics unit, and causes automatic release of the applicator andsimultaneous lock of the electronics unit into the mounting unit.

Although the overall design of the sensor system 10 results in aminiaturized volume as compared to numerous conventional devices, asdescribed in more detail below; the sensor system 310 further enables areduction in volume, as compared to, for example, the sensor system 10described above.

FIGS. 8H and 8I are comparative top views of the sensor system shown inthe alternative embodiment illustrated in FIGS. 8E to 8G and compared tothe embodiments illustrated elsewhere (see FIGS. 1 to 3 and 10 to 12,for example). Namely, the alternative embodiment described withreference to FIGS. 8E to 8G further enables reduced size (e.g., mass,volume, and the like) of the device as compared to certain otherdevices. It has been discovered that the size (including volume and/orsurface area) of the device can affect the function of the device. Forexample, motion of the mounting unit/electronics unit caused by externalinfluences (e.g., bumping or other movement on the skin) is translatedto the sensor in vivo, causing motion artifact (e.g., an effect on thesignal, or the like). Accordingly, by enabling a reduction of size, amore stable signal with overall improved patient comfort can beachieved.

Accordingly, slide-in system 310 described herein, including the systemsand methods for inserting the sensor and connecting the electronics unitto the mounting unit, enables the mounting unit 316/electronics unit 314subassembly to have a volume of less than about 10 cm³, more preferablyless than about 8 cm³, and even more preferably less than about 6 cm³, 5cm³, or 4 cm³ or less. In general, the mounting unit 316/electronicsunit 314 subassembly comprises a first major surface and a second majorsurface opposite the first major surface. The first and second majorsurfaces together preferably account for at least about 50% of thesurface area of the device; the first and second major surfaces eachdefine a surface area, wherein the surface area of each major surface isless than or equal to about 10 cm², preferably less than or equal toabout 8 cm², and more preferably less than or equal to about 6.5 cm², 6cm², 5.5 cm², 5 cm², 4.5 cm², or 4 cm² or less. Typically, the mountingunit 316/electronics unit 314 subassembly has a length 320 of less thanabout 40 mm by a width 322 of less than about 20 mm and a thickness ofless than about 10 mm, and more preferably a length 320 less than orequal to about 35 mm by a width 322 less than or equal to about 18 mm bya thickness of less than or equal to about 9 mm.

In some embodiments, the mounting unit 14/electronics unit 16 assemblyhas the following dimensional properties: preferably a length of about 6cm or less, more preferably about 5 cm or less, more preferably stillabout 4.6 cm or less, even more preferably 4 cm or less, and mostpreferably about 3 cm or less; preferably a width of about 5 cm or less,more preferably about 4 cm or less, even more preferably 3 cm or less,even more preferably still about 2 cm or less, and most preferably about1.5 cm or less; and/or preferably a thickness of about 2 cm or less,more preferably about 1.3 cm or less, more preferably still about 1 cmor less, even more preferably still about 0.7 cm or less, and mostpreferably about 0.5 cm or less. The mounting unit 14/electronics unit16 assembly preferably has a volume of about 20 cm³ or less, morepreferably about 10 cm³ or less, more preferably still about 5 cm³ orless, and most preferably about 3 cm³ or less; and preferably weighs 12g or less, more preferably about 9 g or less, and most preferably about6 g or less, although in some embodiments the electronics unit may weighmore than about 12 g, e.g., up to about 25 g, 45 g, or 90 g.

In some embodiments, the sensor 32 exits the base of the mounting unit14 at a location distant from an edge of the base. In some embodiments,the sensor 32 exits the base of the mounting unit 14 at a locationsubstantially closer to the center than the edges thereof. While notwishing to be bound by theory, it is believed that by providing an exitport for the sensor 32 located away from the edges, the sensor 32 can beprotected from motion between the body and the mounting unit, snaggingof the sensor by an external source, and/or environmental contaminants(e.g., microorganisms) that can migrate under the edges of the mountingunit. In some embodiments, the sensor exits the mounting unit away froman outer edge of the device. FIG. 23 shows transcutaneous glucose sensordata and corresponding blood glucose values obtained over approximatelyseven days in a human, wherein the transcutaneous glucose sensor datawas configured with an exit port situated at a location substantiallycloser to the center than the edges of the base.

In some alternative embodiments, however, the sensor exits the mountingunit 14 at an edge or near an edge of the device. In some embodiments,the mounting unit is configured such that the exit port (location) ofthe sensor is adjustable; thus, in embodiments wherein the depth of thesensor insertion is adjustable, six-degrees of freedom can thereby beprovided.

Extensible Adhesive Pad

In certain embodiments, an adhesive pad is used with the sensor system.A variety of design parameters are desirable when choosing an adhesivepad for the mounting unit. For example: 1) the adhesive pad can bestrong enough to maintain full contact at all times and during allmovements (devices that release even slightly from the skin have agreater risk of contamination and infection), 2) the adhesive pad can bewaterproof or water permeable such that the host can wear the deviceeven while heavily perspiring, showering, or even swimming in somecases, 3) the adhesive pad can be flexible enough to withstand linearand rotational forces due to host movements, 4) the adhesive pad can becomfortable for the host, 5) the adhesive pad can be easily releasableto minimize host pain, 6) and/or the adhesive pad can be easilyreleasable so as to protect the sensor during release. Unfortunately,these design parameters are difficult to simultaneously satisfy usingknown adhesive pads, for example, strong medical adhesive pads areavailable but are usually non-precise (for example, requiringsignificant “ripping” force during release) and can be painful duringrelease due to the strength of their adhesion.

Therefore, the preferred embodiments provide an adhesive pad 8′ formounting the mounting unit onto the host, including a sufficientlystrong medical adhesive pad that satisfies one or more strength andflexibility requirements described above, and further provides a foreasy, precise and pain-free release from the host's skin. FIG. 9A is aside view of the sensor assembly, illustrating the sensor implanted intothe host with mounting unit adhered to the host's skin via an adhesivepad in one embodiment. Namely, the adhesive pad 8′ is formed from anextensible material that can be removed easily from the host's skin bystretching it lengthwise in a direction substantially parallel to (or upto about 35 degrees from) the plane of the skin. It is believed thatthis easy, precise, and painless removal is a function of both the highextensibility and easy stretchability of the adhesive pad.

In one embodiment, the extensible adhesive pad includes a polymeric foamlayer or is formed from adhesive pad foam. It is believed that theconformability and resiliency of foam aids in conformation to the skinand flexibility during movement of the skin. In another embodiment, astretchable solid adhesive pad, such as a rubber-based or anacrylate-based solid adhesive pad can be used. In another embodiment,the adhesive pad comprises a film, which can aid in increasing loadbearing strength and rupture strength of the adhesive pad

FIGS. 9B to 9C illustrate initial and continued release of the mountingunit from the host's skin by stretching the extensible adhesive pad inone embodiment. To release the device, the backing adhesive pad ispulled in a direction substantially parallel to (or up to about 35degrees from) the plane of the device. Simultaneously, the extensibleadhesive pad stretches and releases from the skin in a relatively easyand painless manner.

In one implementation, the mounting unit is bonded to the host's skinvia a single layer of extensible adhesive pad 8′, which is illustratedin FIGS. 9A to 9C. The extensible adhesive pad includes a substantiallynon-extensible pull-tab 52, which can include a light adhesive pad layerthat allows it to be held on the mounting unit 14 prior to release.Additionally, the adhesive pad can further include a substantiallynon-extensible holding tab 54, which remains attached to the mountingunit during release stretching to discourage complete and/oruncontrolled release of the mounting unit from the skin.

In one alternative implementation, the adhesive pad 8′ includestwo-sides, including the extensible adhesive pad and a backing adhesivepad (not shown). In this embodiment, the backing adhesive pad is bondedto the mounting unit's back surface 25 while the extensible adhesive pad8′ is bonded to the host's skin. Both adhesive pads provide sufficientstrength, flexibility, and waterproof or water permeable characteristicsappropriate for their respective surface adhesion. In some embodiments,the backing and extensible adhesive pads are particularly designed withan optimized bond for their respective bonding surfaces (namely, themounting unit and the skin).

In another alternative implementation, the adhesive pad 8′ includes adouble-sided extensible adhesive pad surrounding a middle layer orbacking layer (not shown). The backing layer can comprise a conventionalbacking film or can be formed from foam to enhance comfort,conformability, and flexibility. Preferably, each side of thedouble-sided adhesive pad is respectively designed for appropriatebonding surface (namely, the mounting unit and skin). A variety ofalternative stretch-release configurations are possible. Controlledrelease of one or both sides of the adhesive pad can be facilitated bythe relative lengths of each adhesive pad side, by incorporation of anon-adhesive pad zone, or the like.

FIGS. 10A and 10B are perspective and side cross-sectional views,respectively, of the mounting unit immediately following sensorinsertion and release of the applicator from the mounting unit. In oneembodiment, such as illustrated in FIGS. 10A and 10B, the contactsubassembly 26 is held in its insertion position, substantially at theinsertion angle α of the sensor. Maintaining the contact subassembly 26at the insertion angle α during insertion enables the sensor 32 to beeasily inserted straight through the contact subassembly 26. The contactsubassembly 26 further includes a hinge 38 that allows movement of thecontact subassembly 26 from an angled to a flat position. The term“hinge,” as used herein, is a broad term and is used in its ordinarysense, including, without limitation, a mechanism that allowsarticulation of two or more parts or portions of a device. The term isbroad enough to include a sliding hinge, for example, a ball and detenttype hinging mechanism.

Although the illustrated embodiments describe a fixed insertion angledesigned into the applicator, alternative embodiments can design theinsertion angle into other components of the system. For example, theinsertion angle can be designed into the attachment of the applicatorwith the mounting unit, or the like. In some alternative embodiments, avariety of adjustable insertion angles can be designed into the systemto provide for a variety of host dermis configurations.

FIG. 10B illustrates the sensor 32 extending from the mounting unit 14by a preselected distance, which defines the depth of insertion of thesensor into the host. The dermal and subcutaneous make-up of animals andhumans is variable and a fixed depth of insertion may not be appropriatefor all implantations. Accordingly, in an alternative embodiment, thedistance that the sensor extends from the mounting unit is adjustable toaccommodate a variety of host body-types. For example, the applicator 12can be designed with a variety of adjustable settings, which control thedistance that the needle 72 (and therefore the sensor 32) extends uponsensor insertion. One skilled in the art appreciates a variety of meansand mechanisms can be employed to accommodate adjustable sensorinsertion depths, which are considered within the scope of the preferredembodiments. The preferred insertion depth is from about 0.1 mm or lessto about 2 cm or more, preferably from about 0.15, 0.2, 0.25, 0.3, 0.35,0.4, or 0.45 mm to about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, or 1.9 cm.

FIGS. 11A and 11B are perspective and side cross-sectional views,respectively, of the mounting unit after articulating the contactsubassembly to its functional position (which is also referred to as aninserted, implanted, or sensing position). The hinge 38 enables thecontact subassembly 26 to tilt from its insertion position (FIG. 10) toits functional position (FIG. 11) by pressing downward on the contactsubassembly, for example. Certain embodiments provide this pivotalmovement via two separate pieces (the contact subassembly 26 and themounting unit 14 connected by a hinge, for example, a mechanical oradhesive pad joint or hinge. A variety of pivoting, articulating, and/orhinging mechanisms can be employed with the sensors of preferredembodiments. For example, the hinge can be formed as a part of thecontact subassembly 26. The contact subassembly can be formed from aflexible piece of material (such as silicone, urethane rubber, or otherflexible or elastomeric material), wherein the material is sufficientlyflexible to enable bending or hinging of the contact subassembly from anangle appropriate for insertion (FIGS. 10A and 10B) to a lowerfunctional configuration (FIGS. 11A and 11B).

The relative pivotal movement of the contact subassembly isadvantageous, for example, for enabling the design of a low profiledevice while providing support for an appropriate needle insertionangle. In its insertion position, the sensor system is designed for easysensor insertion while forming a stable electrical connection with theassociated contacts 28. In its functional position, the sensor systemmaintains a low profile for convenience, comfort, and discreetnessduring use. Thus, the sensor systems of preferred embodiments areadvantageously designed with a hinging configuration to provide anoptimum guided insertion angle while maintaining a low profile deviceduring sensor use.

In some embodiments, a shock-absorbing member or feature is incorporatedinto the design of the sensor and configured to absorb movement of thein vivo and/or ex vivo portion of the sensor. Conventional analytesensors can suffer from motion-related artifact associated with hostmovement when the host is using the device. For example, when atranscutaneous analyte sensor is inserted into the host, variousmovements on the sensor (for example, relative movement between the invivo portion and the ex vivo portion and/or movement within the host)create stresses on the device and can produce noise in the sensorsignal. Accordingly in some embodiments, a shock-absorbing member islocated on the sensor/mounting unit in a location that absorbs stressesassociated with the above-described movement.

In the preferred embodiments, the sensor 32 bends from a substantiallystraight to substantially bent configuration upon pivoting of thecontact subassembly from the insertion to functional position. Thesubstantially straight sensor configuration during insertionadvantageously provides ease of sensor insertion, while the substantialbend in the sensor in its functional position advantageously providesstability on the proximal end of the sensor with flexibility/mobility onthe distal end of the sensor. Additionally, motion within the mountingunit (e.g., caused by external forces to the mounting unit, movement ofthe skin, and the like) does not substantially translate to the in vivoportion of the sensor. Namely, the bend formed within the sensor 32functions to break column strength, causing flexion that effectivelyabsorbs movements on the sensor during use. Additionally, the sensor canbe designed with a length such that when the contact subassembly 26 ispivoted to its functional position (FIG. 10B), the sensor pushes forwardand flexes, allowing it to absorb motion between the in vivo and ex vivoportions of the sensor. It is believed that both of the above advantagesminimize motion artifact on the sensor signal and/or minimize damage tothe sensor caused by movement, both of which (motion artifact anddamage) have been observed in conventional transcutaneous sensors.

In some alternative embodiments, the shock-absorbing member can be anexpanding and contracting member, such as a spring, accordion,telescoping, or bellows-type device. In general, the shock absorbingmember can be located such that relative movement between the sensor,the mounting unit, and the host is absorbed without (or minimally)affecting the connection of the sensor to the mounting unit and/or thesensor stability within the implantation site; for example, theshock-absorbing member can be formed as a part of or connected to thesensor 32.

FIGS. 12A to 12C are perspective and side views of a sensor systemincluding the mounting unit 14 and electronics unit 16 attached thereto.After sensor insertion, the transcutaneous analyte sensor system 10measures a concentration of an analyte or a substance indicative of theconcentration or presence of the analyte as described above. Althoughthe examples are directed to a glucose sensor, the analyte sensor can bea sensor capable of determining the level of any suitable analyte in thebody, for example, oxygen, lactase, insulin, hormones, cholesterol,medicaments, viruses, or the like. Once the electronics unit 16 isconnected to the mounting unit 14, the sensor 32 is able to measurelevels of the analyte in the host.

Detachable connection between the mounting unit 14 and electronics unit16 provides improved manufacturability, namely, the relativelyinexpensive mounting unit 14 can be disposed of when replacing thesensor system after its usable life, while the relatively more expensiveelectronics unit 16 can be reusable with multiple sensor systems. Incertain embodiments, the electronics unit 16 is configured withprogramming, for example, initialization, calibration reset, failuretesting, or the like, each time it is initially inserted into the cavityand/or each time it initially communicates with the sensor 32. However,an integral (non-detachable) electronics unit can be configured as isappreciated by one skilled in the art.

Referring to the mechanical fit between the mounting unit 14 and theelectronics unit 16 (and/or applicator 12), a variety of mechanicaljoints are contemplated, for example, snap fit, interference fit, orslide fit. In the illustrated embodiment of FIGS. 12A to 12C, tabs 120are provided on the mounting unit 14 and/or electronics unit 16 thatenable a secure connection therebetween. The tabs 120 of the illustratedembodiment can improve ease of mechanical connection by providingalignment of the mounting unit and electronics unit and additional rigidsupport for force and counter force by the user (e.g., fingers) duringconnection. However, other configurations with or without guiding tabsare contemplated, such as illustrated in FIGS. 10 and 11, for example.

In some circumstances, a drift of the sensor signal can causeinaccuracies in sensor performance and/or require re-calibration of thesensor. Accordingly, it can be advantageous to provide a sealant,whereby moisture (e.g., water and water vapor) cannot substantiallypenetrate to the sensor and its connection to the electrical contacts.The sealant described herein can be used alone or in combination withthe sealing member 36 described in more detail above, to seal the sensorfrom moisture in the external environment.

Preferably, the sealant fills in holes, crevices, or other void spacesbetween the mounting unit 14 and electronics unit 16 and/or around thesensor 32 within the mounting unit 32. For example, the sealant cansurround the sensor in the portion of the sensor 32 that extends throughthe contacts 28. Additionally, the sealant can be disposed within theadditional void spaces, for example a hole 122 that extends through thesealing member 36.

Preferably, the sealant comprises a water impermeable material orcompound, for example, oil, grease, or gel. In one exemplary embodiment,the sealant, which also can be referred to as a lubricant in certainembodiments, comprises petroleum jelly and is used to provide a moisturebarrier surrounding the sensor 32. In one experiment, petroleum jellywas liquefied by heating, after which a sensor 32 was immersed into theliquefied petroleum jelly to coat the outer surfaces thereof. The sensorwas then assembled into a housing and inserted into a host, during whichdeployment the sensor was inserted through the electrical contacts 28and the petroleum jelly conforming therebetween. Sensors incorporatingpetroleum jelly, such as described above, when compared to sensorswithout the petroleum jelly moisture barrier exhibited less or no signaldrift over time when studied in a humid or submersed environment. Whilenot wishing to be bound by theory, it is believed that incorporation ofa moisture barrier surrounding the sensor, especially between the sensorand its associated electrical contacts, reduces or eliminates theeffects of humidity on the sensor signal. The viscosity of grease oroil-based moisture barriers allows penetration into and through evensmall cracks or crevices within the sensor and mounting unit, displacingmoisture and thereby increasing the sealing properties thereof. U.S.Pat. No. 4,259,540 and U.S. Pat. No. 5,285,513 disclose materialssuitable for use as a water impermeable material (sealant).

Referring to the electrical fit between the sensor 32 and theelectronics unit 16, contacts 28 (through which the sensor extends) areconfigured to electrically connect with mutually engaging contacts onthe electronics unit 16. A variety of configurations are contemplated;however, the mutually engaging contacts operatively connect upondetachable connection of the electronics unit 16 with the mounting unit14, and are substantially sealed from external moisture by sealingmember 36. Even with the sealing member, some circumstances can existwherein moisture can penetrate into the area surrounding the sensor 32and or contacts, for example, exposure to a humid or wet environment(e.g., caused by sweat, showering, or other environmental causes). Ithas been observed that exposure of the sensor to moisture can be a causeof baseline signal drift of the sensor over time. For example in aglucose sensor, the baseline is the component of a glucose sensor signalthat is not related to glucose (the amount of signal if no glucose ispresent), which is ideally constant over time. However, somecircumstances my exist wherein the baseline can fluctuate over time,also referred to as drift, which can be caused, for example, by changesin a host's metabolism, cellular migration surrounding the sensor,interfering species, humidity in the environment, and the like.

In some embodiments, the mounting unit is designed to provideventilation (e.g., a vent hole 124) between the exit-site and thesensor. In certain embodiments, a filter (not shown) is provided in thevent hole 124 that allows the passage of air, while preventingcontaminants from entering the vent hole 124 from the externalenvironment. While not wishing to be bound by theory, it is believedthat ventilation to the exit-site (or to the sensor 32) can reduce oreliminate trapped moisture or bacteria, which can otherwise increase thegrowth and/or lifetime of bacteria adjacent to the sensor.

In some alternative embodiments, a sealing material is provided, whichseals the needle and/or sensor from contamination of the externalenvironment during and after sensor insertion. For example, one problemencountered in conventional transcutaneous devices is infection of theexit-site of the wound. For example, bacteria or contaminants canmigrate from ex vivo, for example, any ex vivo portion of the device orthe ex vivo environment, through the exit-site of the needle/sensor, andinto the subcutaneous tissue, causing contamination and infection.Bacteria and/or contaminants can originate from handling of the device,exposed skin areas, and/or leakage from the mounting unit (external to)on the host. In many conventional transcutaneous devices, there existssome path of migration for bacteria and contaminants to the exit-site,which can become contaminated during sensor insertion or subsequenthandling or use of the device. Furthermore, in some embodiments of atranscutaneous analyte sensor, the insertion-aiding device (for example,needle) is an integral part of the mounting unit; namely, the devicestores the insertion device after insertion of the sensor, which isisolated from the exit-site (namely, point-of-entry of the sensor) afterinsertion.

Accordingly, these alternative embodiments provide a sealing material onthe mounting unit, interposed between the housing and the skin, whereinthe needle and/or sensor are adapted to extend through, and be sealedby, the sealing material. The sealing material is preferably formed froma flexible material that substantially seals around the needle/sensor.Appropriate flexible materials include malleable materials, elastomers,gels, greases, or the like (e.g., see U.S. Pat. No. 4,259,540 and U.S.Pat. No. 5,285,513). However, not all embodiments include a sealingmaterial, and in some embodiments a clearance hole or other spacesurrounding the needle and/or sensor is preferred.

In one embodiment, the base 24 of the mounting unit 14 is formed from aflexible material, for example silicone, which by its elastomericproperties seals the needle and/or sensor at the exit port 126, such asis illustrated in FIGS. 11A and 11B. Thus, sealing material can beformed as a unitary or integral piece with the back surface 25 of themounting unit 14, or with an adhesive pad 8 on the back surface of themounting unit, however alternatively can be a separate part secured tothe device. In some embodiments, the sealing material can extend throughthe exit port 126 above or below the plane of the adhesive pad surface,or the exit port 126 can comprise a septum seal such as those used inthe medical storage and disposal industries (for example, silica gelsandwiched between upper and lower seal layers, such as layerscomprising chemically inert materials such as PTFE). A variety of knownseptum seals can be implemented into the exit port of the preferredembodiments described herein. Whether the sealing material is integralwith or a separate part attached to the mounting unit 14, the exit port126 is advantageously sealed so as to reduce or eliminate the migrationof bacteria or other contaminants to or from the exit-site of the woundand/or within the mounting unit.

During use, a host or caretaker positions the mounting unit at theappropriate location on or near the host's skin and prepares for sensorinsertion. During insertion, the needle aids in sensor insertion, afterwhich the needle is retracted into the mounting unit leaving the sensorin the subcutaneous tissue. In this embodiment, the exit-port 126includes a layer of sealing material, such as a silicone membrane, thatencloses the exit-port in a configuration that protects the exit-sitefrom contamination that can migrate from the mounting unit or spacingexternal to the exit-site. Thus, when the sensor 32 and/or needle 72extend through, for example, an aperture or a puncture in the sealingmaterial, to provide communication between the mounting unit andsubcutaneous space, a seal is formed therebetween. Elastomeric sealingmaterials can be advantageous in some embodiments because the elasticityprovides a conforming seal between the needle/sensor and the mountingunit and/or because the elasticity provides shock-absorbing qualitiesallowing relative movement between the device and the various layers ofthe host's tissue, for example.

In some alternative embodiments, the sealing material includes abioactive agent incorporated therein. Suitable bioactive agents includethose which are known to discourage or prevent bacteria and infection,for example, anti-inflammatory, antimicrobials, antibiotics, or thelike. It is believed that diffusion or presence of a bioactive agent canaid in prevention or elimination of bacteria adjacent to the exit-site.

In practice, after the sensor 32 has been inserted into the host'stissue, and an electrical connection formed by mating the electronicsunit 16 to the mounting unit 14, the sensor measures an analyteconcentration continuously or continually, for example, at an intervalof from about fractions of a second to about 10 minutes or more.

FIG. 13 is an exploded perspective view of one exemplary embodiment of acontinuous glucose sensor 1310A. In this embodiment, the sensor ispreferably wholly implanted into the subcutaneous tissue of a host, suchas described in co-pending patent application Ser. No. 10/885,476 filedJul. 6, 2004 and entitled “SYSTEMS AND METHODS FOR MANUFACTURE OF ANANALYTE-MEASURING DEVICE INCLUDING A MEMBRANE SYSTEM”; U.S. PublicationNo. US-2005-0245799-A1; U.S. Publication No. US-2005-0192557-A1; U.S.Publication No. US-2004-0199059-A1; U.S. Publication No.US-2005-0027463-A1; and U.S. Pat. No. 6,001,067. In this exemplaryembodiment, a body 1320 and a sensing region 1321 house the electrodes1322 and sensor electronics (see FIG. 14). The three electrodes 1322 areoperably connected to the sensor electronics (see FIG. 14) and arecovered by a sensing membrane 1323 and a biointerface membrane 1324,which are attached by a clip 1325.

In one embodiment, the three electrodes 1322 include a platinum workingelectrode, a platinum counter electrode, and a silver/silver chloridereference electrode. The top ends of the electrodes are in contact withan electrolyte phase (not shown), which is a free-flowing fluid phasedisposed between the sensing membrane 1323 and the electrodes 1322. Thesensing membrane 1323 includes an enzyme, for example, glucose oxidase,and covers the electrolyte phase. The biointerface membrane 1324 coversthe sensing membrane 1323 and serves, at least in part, to protect thesensor 1310A from external forces that can result in environmentalstress cracking of the sensing membrane 1323. U.S. Publication No.US-2005-0112169-A1 describes a biointerface membrane that can be used inconjunction with the preferred embodiments.

In one embodiment, the biointerface membrane 1324 generally includes acell disruptive domain most distal from the electrochemically reactivesurfaces and a cell impermeable domain less distal from theelectrochemically reactive surfaces than the cell disruptive domain. Thecell disruptive domain is preferably designed to support tissueingrowth, disrupt contractile forces typically found in a foreign bodyresponse, encourage vascularity within the membrane, and disrupt theformation of a barrier cell layer. The cell impermeable domain ispreferably resistant to cellular attachment, impermeable to cells, andcomposed of a biostable material.

In one embodiment, the sensing membrane 1323 generally provides one ormore of the following functions: 1) protection of the exposed electrodesurface from the biological environment, 2) diffusion resistance(limitation) of the analyte, 3) a catalyst for enabling an enzymaticreaction, 4) limitation or blocking of interfering species, and 5)hydrophilicity at the electrochemically reactive surfaces of the sensorinterface, such as described in U.S. Publication No. US-2005-0245799-A1.Accordingly, the sensing membrane 1323 preferably includes a pluralityof domains or layers, for example, an electrolyte domain, aninterference domain, an enzyme domain (for example, glucose oxidase), aresistance domain, and can additionally include an oxygen domain (notshown), and/or a bioprotective domain (not shown), such as described inmore detail herein and in U.S. Publication No. US-2005-0245799-A1.However, it is understood that a sensing membrane modified for otherdevices, for example, by including fewer or additional domains is withinthe scope of the preferred embodiments.

In some embodiments, the domains of the biointerface and sensingmembranes are formed from materials such as silicone,polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene,polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene,homopolymers, copolymers, terpolymers of polyurethanes, polypropylene(PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF),polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA),polyether ether ketone (PEEK), polyurethanes, cellulosic polymers,polysulfones and block copolymers thereof including, for example,di-block, tri-block, alternating, random and graft copolymers. U.S.Publication No. US-2005-0245799-A1 describes biointerface and sensingmembrane configurations and materials that can be applied to thepreferred embodiments.

In the illustrated embodiment, the counter electrode is provided tobalance the current generated by the species being measured at theworking electrode. In the case of a glucose oxidase based glucosesensor, the species being measured at the working electrode is H₂O₂.Glucose oxidase catalyzes the conversion of oxygen and glucose tohydrogen peroxide and gluconate according to the following reaction:Glucose+O₂→Gluconate+H₂O₂

The change in H₂O₂ can be monitored to determine glucose concentrationbecause for each glucose molecule metabolized, there is a proportionalchange in the product H₂O₂. Oxidation of H₂O₂ by the working electrodeis balanced by reduction of ambient oxygen, enzyme generated H₂O₂, orother reducible species at the counter electrode. The H₂O₂ produced fromthe glucose oxidase reaction further reacts at the surface of workingelectrode and produces two protons (2H⁺), two electrons (2e⁻), and oneoxygen molecule (O₂).

In one embodiment, a potentiostat is employed to monitor theelectrochemical reaction at the electrochemical cell. The potentiostatapplies a constant potential to the working and reference electrodes todetermine a current value. The current that is produced at the workingelectrode (and flows through the circuitry to the counter electrode) issubstantially proportional to the amount of H₂O₂ that diffuses to theworking electrode. Accordingly, a raw signal can be produced that isrepresentative of the concentration of glucose in the user's body, andtherefore can be utilized to estimate a meaningful glucose value, suchas is described herein.

Sensor Electronics

The following description of sensor electronics associated with theelectronics unit is applicable to a variety of continuous analytesensors, such as non-invasive, minimally invasive, and/or invasive(e.g., transcutaneous and wholly implantable) sensors. For example, thesensor electronics and data processing as well as the receiverelectronics and data processing described below can be incorporated intothe wholly implantable glucose sensor disclosed in U.S. Publication No.US-2005-0245799-A1 and U.S. patent application Ser. No. 10/885,476 filedJul. 6, 2004 and entitled, “SYSTEMS AND METHODS FOR MANUFACTURE OF ANANALYTE-MEASURING DEVICE INCLUDING A MEMBRANE SYSTEM.”

FIG. 14 is a block diagram that illustrates the electronics 132associated with the sensor system 10 in one embodiment. In thisembodiment, a potentiostat 134 is shown, which is operably connected toan electrode system (such as described above) and provides a voltage tothe electrodes, which biases the sensor to enable measurement of ancurrent signal indicative of the analyte concentration in the host (alsoreferred to as the analog portion). In some embodiments, thepotentiostat includes a resistor (not shown) that translates the currentinto voltage. In some alternative embodiments, a current to frequencyconverter is provided that is configured to continuously integrate themeasured current, for example, using a charge counting device.

An A/D converter 136 digitizes the analog signal into a digital signal,also referred to as “counts” for processing. Accordingly, the resultingraw data stream in counts, also referred to as raw sensor data, isdirectly related to the current measured by the potentiostat 134.

A processor module 138 includes the central control unit that controlsthe processing of the sensor electronics 132. In some embodiments, theprocessor module includes a microprocessor, however a computer systemother than a microprocessor can be used to process data as describedherein, for example an ASIC can be used for some or all of the sensor'scentral processing. The processor typically provides semi-permanentstorage of data, for example, storing data such as sensor identifier(ID) and programming to process data streams (for example, programmingfor data smoothing and/or replacement of signal artifacts such as isdescribed in U.S. Publication No. US-2005-0043598-A1). The processoradditionally can be used for the system's cache memory, for example fortemporarily storing recent sensor data. In some embodiments, theprocessor module comprises memory storage components such as ROM, RAM,dynamic-RAM, static-RAM, non-static RAM, EEPROM, rewritable ROMs, flashmemory, or the like.

In some embodiments, the processor module comprises a digital filter,for example, an infinite impulse response (IIR) or finite impulseresponse (FIR) filter, configured to smooth the raw data stream from theA/D converter. Generally, digital filters are programmed to filter datasampled at a predetermined time interval (also referred to as a samplerate). In some embodiments, wherein the potentiostat is configured tomeasure the analyte at discrete time intervals, these time intervalsdetermine the sample rate of the digital filter. In some alternativeembodiments, wherein the potentiostat is configured to continuouslymeasure the analyte, for example, using a current-to-frequency converteras described above, the processor module can be programmed to request adigital value from the A/D converter at a predetermined time interval,also referred to as the acquisition time. In these alternativeembodiments, the values obtained by the processor are advantageouslyaveraged over the acquisition time due the continuity of the currentmeasurement. Accordingly, the acquisition time determines the samplerate of the digital filter. In preferred embodiments, the processormodule is configured with a programmable acquisition time, namely, thepredetermined time interval for requesting the digital value from theA/D converter is programmable by a user within the digital circuitry ofthe processor module. An acquisition time of from about 2 seconds toabout 512 seconds is preferred; however any acquisition time can beprogrammed into the processor module. A programmable acquisition time isadvantageous in optimizing noise filtration, time lag, andprocessing/battery power.

Preferably, the processor module is configured to build the data packetfor transmission to an outside source, for example, an RF transmissionto a receiver as described in more detail below. Generally, the datapacket comprises a plurality of bits that can include a preamble, aunique identifier identifying the electronics unit, the receiver, orboth, (e.g., sensor ID code), data (e.g., raw data, filtered data,and/or an integrated value) and/or error detection or correction.Preferably, the data (transmission) packet has a length of from about 8bits to about 128 bits, preferably about 48 bits; however, larger orsmaller packets can be desirable in certain embodiments. The processormodule can be configured to transmit any combination of raw and/orfiltered data. In one exemplary embodiment, the transmission packetcontains a fixed preamble, a unique ID of the electronics unit, a singlefive-minute average (e.g., integrated) sensor data value, and a cyclicredundancy code (CRC).

In some embodiments, the processor module further comprises atransmitter portion that determines the transmission interval of thesensor data to a receiver, or the like. In some embodiments, thetransmitter portion, which determines the interval of transmission, isconfigured to be programmable. In one such embodiment, a coefficient canbe chosen (e.g., a number of from about 1 to about 100, or more),wherein the coefficient is multiplied by the acquisition time (orsampling rate), such as described above, to define the transmissioninterval of the data packet. Thus, in some embodiments, the transmissioninterval is programmable from about 2 seconds to about 850 minutes, morepreferably from about 30 second to about 5 minutes; however, anytransmission interval can be programmable or programmed into theprocessor module. However, a variety of alternative systems and methodsfor providing a programmable transmission interval can also be employed.By providing a programmable transmission interval, data transmission canbe customized to meet a variety of design criteria (e.g., reducedbattery consumption, timeliness of reporting sensor values, etc.)

Conventional glucose sensors measure current in the nanoAmp range. Incontrast to conventional glucose sensors, the preferred embodiments areconfigured to measure the current flow in the picoAmp range, and in someembodiments, femtoAmps. Namely, for every unit (mg/dL) of glucosemeasured, at least one picoAmp of current is measured. Preferably, theanalog portion of the A/D converter 136 is configured to continuouslymeasure the current flowing at the working electrode and to convert thecurrent measurement to digital values representative of the current. Inone embodiment, the current flow is measured by a charge counting device(e.g., a capacitor). Preferably, a charge counting device provides avalue (e.g., digital value) representative of the current flowintegrated over time (e.g., integrated value). In some embodiments, thevalue is integrated over a few seconds, a few minutes, or longer. In oneexemplary embodiment, the value is integrated over 5 minutes; however,other integration periods can be chosen. Thus, a signal is provided,whereby a high sensitivity maximizes the signal received by a minimalamount of measured hydrogen peroxide (e.g., minimal glucose requirementswithout sacrificing accuracy even in low glucose ranges), reducing thesensitivity to oxygen limitations in vivo (e.g., in oxygen-dependentglucose sensors).

In some embodiments, the electronics unit is programmed with a specificID, which is programmed (automatically or by the user) into a receiverto establish a secure wireless communication link between theelectronics unit and the receiver. Preferably, the transmission packetis Manchester encoded; however, a variety of known encoding techniquescan also be employed.

A battery 144 is operably connected to the sensor electronics 132 andprovides the power for the sensor. In one embodiment, the battery is alithium manganese dioxide battery; however, any appropriately sized andpowered battery can be used (for example, AAA, nickel-cadmium,zinc-carbon, alkaline, lithium, nickel-metal hydride, lithium-ion,zinc-air, zinc-mercury oxide, silver-zinc, and/or hermetically-sealed).In some embodiments, the battery is rechargeable, and/or a plurality ofbatteries can be used to power the system. The sensor can betranscutaneously powered via an inductive coupling, for example. In someembodiments, a quartz crystal 96 is operably connected to the processor138 and maintains system time for the computer system as a whole, forexample for the programmable acquisition time within the processormodule.

Optional temperature probe 140 is shown, wherein the temperature probeis located on the electronics assembly or the glucose sensor itself. Thetemperature probe can be used to measure ambient temperature in thevicinity of the glucose sensor. This temperature measurement can be usedto add temperature compensation to the calculated glucose value.

An RF module 148 is operably connected to the processor 138 andtransmits the sensor data from the sensor to a receiver within awireless transmission 150 via antenna 152. In some embodiments, a secondquartz crystal 154 provides the time base for the RF carrier frequencyused for data transmissions from the RF transceiver. In some alternativeembodiments, however, other mechanisms, such as optical, infraredradiation (IR), ultrasonic, or the like, can be used to transmit and/orreceive data.

In the RF telemetry module of the preferred embodiments, the hardwareand software are designed for low power requirements to increase thelongevity of the device (for example, to enable a life of from about 3to about 24 months, or more) with maximum RF transmittance from the invivo environment to the ex vivo environment for wholly implantablesensors (for example, a distance of from about one to ten meters ormore). Preferably, a high frequency carrier signal of from about 402 MHzto about 433 MHz is employed in order to maintain lower powerrequirements. In some embodiments, the RF module employs a one-way RFcommunication link to provide a simplified ultra low power datatransmission and receiving scheme. The RF transmission can be OOK or FSKmodulated, preferably with a radiated transmission power (EIRP) fixed ata single power level of typically less than about 100 microwatts,preferably less than about 75 microwatts, more preferably less thanabout 50 microwatts, and most preferably less than about 25 microwatts.

Additionally, in wholly implantable devices, the carrier frequency isadapted for physiological attenuation levels, which is accomplished bytuning the RF module in a simulated in vivo environment to ensure RFfunctionality after implantation; accordingly, the preferred glucosesensor can sustain sensor function for 3 months, 6 months, 12 months, or24 months or more.

When a sensor is first implanted into host tissue, the sensor andreceiver are initialized. This is referred to as start-up mode, andinvolves optionally resetting the sensor data and calibrating the sensor32. In selected embodiments, mating the electronics unit 16 to themounting unit triggers a start-up mode. In other embodiments, thestart-up mode is triggered by the receiver, which is described in moredetail with reference to FIG. 21, below.

Preferably, the electronics unit 16 indicates to the receiver (FIGS. 15and 17) that calibration is to be initialized (or re-initialized). Theelectronics unit 16 transmits a series of bits within a transmitted datapacket wherein a sensor code can be included in the periodictransmission of the device. The status code is used to communicatesensor status to the receiving device. The status code can be insertedinto any location in the transmitted data packet, with or without othersensor information. In one embodiment, the status code is designed to beunique or near unique to an individual sensor, which can be accomplishedusing a value that increments, decrements, or changes in some way afterthe transmitter detects that a sensor has been removed and/or attachedto the transmitter. In an alternative embodiment, the status code can beconfigured to follow a specific progression, such as a BCDinterpretation of a Gray code.

In some embodiments, the sensor electronics 132 are configured to detecta current drop to zero in the working electrode 44 associated withremoval of a sensor 32 from the host (or the electronics unit 16 fromthe mounting unit 14), which can be configured to trigger an incrementof the status code. If the incremented value reaches a maximum, it canbe designed to roll over to 0. In some embodiments, the sensorelectronics are configured to detect a voltage change cycle associatedwith removal and/or re-insertion of the sensor, which can be sensed inthe counter electrode (e.g., of a three-electrode sensor), which can beconfigured to trigger an increment of the status code.

In some embodiments, the sensor electronics 132 can be configured tosend a special value (for example, 0) that indicates that theelectronics unit is not attached when removal of the sensor (orelectronics unit) is detected. This special value can be used to triggera variety of events, for example, to halt display of analyte values.Incrementing or decrementing routines can be used to skip this specialvalue.

Information Tag

In certain embodiments, it can be useful to provide readable informationin or on the sensor system (e.g., the mounting unit and/or sensorpackaging) to identify characteristics about the sensor. Although thefollowing description is mostly drawn to providing sensor information onthe mounting unit or the packaging, other parts of the sensor system canhouse the information tag, for example, the tag can be embedded withinthe electronics unit. Additionally, when implemented in a whollyimplantable sensor (see, e.g., U.S. Publication No. US-2005-0245799-A1),the information tag can be embedded in any portion of the implantabledevice (e.g., electronics or on a chip within the body of theimplantable device).

In general, the information tag includes information about the sensormanufacture (e.g., lot, date, and/or the like), calibration (e.g., slopeor sensitivity, lot, and/or the like), identification (e.g., uniquenumber, part number, and/or the like), expiration (e.g., date ofexpiration of the sensor, and/or the like), intended sensor duration(e.g., insertion or implantation time period), archived data (e.g., mostrecent 1 hour of analyte data), license code/key information, and thelike. In one embodiment, the information tag is provided on a single-useportion of the device (e.g., the mounting unit) and the sensorinformation is related to the single-use device, for example,information such as license code, sensor duration, and expirationinformation that can be useful to an associated reusable device (e.g.,receiver). Preferably, the information tag is readable by a device orperson in a manner that permits easy data transfer (e.g., of the licensecode or intended sensor duration) with minimal user interaction.Preferably, the information tag has an electronic component including amemory for storing the sensor information; however, visual informationtags (e.g., barcodes) can also be employed. In some embodiments, theinformation tag comprises a readable chip, wherein the chip transmitsinformation using one or more of the following technologies: wired(e.g., via a serial or parallel port), radio frequency, infrared,optical, acoustic, magnetic induction, and the like.

In one embodiment, the information tag includes a hardware key, alsoreferred to as a hardware license key. Preferably, a hardware keyincludes a single-use (e.g., disposable) connector piece with anencrypted chip (e.g., encrypted to avoid copying); however reusablehardware keys can also be employed. In some embodiments, the hardwarekey is referred to as a “dongle.” In general, a dongle is a smallhardware device that connects to a computer system (e.g., the receiver)to authenticate, manipulate, or otherwise control some piece of softwaretherein. The hardware key can be non-specific to a receiver (e.g., usedwith any number of different receivers, enabling low-cost manufacturingand ease of utilization). The chip inside the dongle typically includeslicense code information described above, for example, a number ofinsertion periods (e.g., 5 insertion periods for a hardware key packagedin a 5-sensor package) and/or length of insertion periods (e.g., 3-daysfor a 3-day sensor).

In one exemplary embodiment, the information tag includes a hardware keycomprising an encrypted flash memory chip (e.g., a flash memory productsuch as manufactured by Atmel Corporation, San Jose, Calif.), whichprovides a secure, encrypted, easy-to-use method of preventingout-of-label use (e.g., extended use beyond that specified on the label)and/or reuse of sensor(s). In another exemplary embodiment, theinformation tag includes a hardware key comprising a serialidentification chip (e.g., a serial memory product such as manufacturedby Maxim Integrated Products, Inc. of Sunnyvale, Calif.), also referredto as a one-wire interface. In these embodiments, a port is provided onthe sensor system (e.g., the receiver) that receives the hardware keyand reads the information thereon. In some embodiments, the informationtag is provided in or on the sensor system packaging.

As an example, in practice, a user receives a hardware key inside of apackage containing one or more sensors, for example, five sensors. Theuser plugs the hardware key into the port (e.g., serial or parallelport) on the receiver. Once the hardware key is operatively connected tothe receiver, the receiver runs a validation (e.g., authentication) toensure the key is authentic (e.g., not a “knock-off”), reads theinformation therein (e.g., license information such as number of and/orduration of sensor insertions), and optionally marks or erases at leasta portion of the chip's memory to prevent unintended use of the key (forexample, the key can be designed for single-use only). The receiver thenprocesses the information, for example, by limiting the sensor(s) to itsprescribed usage(s). In one exemplary embodiment, a hardware keyassociated with five 3-day sensors allows fifteen days of sensor use.Preferably, the number of licenses will be decremented to prevent reuseon another receiver.

In an alternative embodiment, the information tag includes a RadioFrequency Identification (RFID) chip. RFID is a wireless data collectiontechnology that uses electronic tags for storing data. RFID tags (orchips) are read when they are within the proximity of a transmittedradio signal. Because RFID tags can hold substantial amounts of data,the RFID tag can be used for tracking individual items. There are twotypes of RFID tags: passive and active. “Passive” tags have no powersource but use the electromagnetic waves from a reader (e.g., thereceiver) up to approximately 15 feet away to transmit back theircontents. “Active” tags use a battery to transmit up to about 1,500feet.

In some embodiments, an information tag is embedded in or on the on-skinhousing (e.g., mounting unit and/or transmitter). Preferably, thereceiver is configured to interrogate the information tag to obtainparticular information; however, an information tag with two-waycommunication can also be employed. In one embodiment, the informationtag includes a serial number or other identification information for thesensor. In another embodiment, the information tag is configured toinitialize the sensor/receiver. In another embodiment, the informationtag includes a calibration code that is used by the receiver duringcalibration of the sensor. In another embodiment, the information tagincludes expiration information. In yet another embodiment, theinformation tag includes a key or license code. In alternativeembodiments, the information tag uniquely identifies the sensor 32 andallows the transmitter to adjust the sensor ID code accordingly and/orto transmit the unique identifier to the receiver 158. The informationtag can be configured to include various combinations of theabove-referenced information, or additional information useful tooperation of the sensor.

In some embodiments, the electronics unit 16 is configured to includeadditional contacts, which are designed to sense a specific resistance,or passive value, in the sensor system while the electronics unit isattached to the mounting unit. Preferably, these additional contacts areconfigured to detect information about a sensor, for example, whetherthe sensor is operatively connected to the mounting unit, the sensor'sID, a calibration code, or the like. For example, subsequent to sensingthe passive value, the sensor electronics can be configured to changethe sensor ID code by either mapping the value to a specific code, orinternally detecting that the code is different and adjusting the sensorID code in a predictable manner. As another example, the passive valuecan include information on parameters specific to a sensor (such as invitro sensitivity information as described elsewhere herein).

In some embodiments, the electronics unit 16 includes additionalcontacts configured to communicate with a chip disposed in the mountingunit 14. In this embodiment, the chip is designed with a unique ornear-unique signature that can be detected by the electronics unit 16and noted as different, and/or transmitted to the receiver 158 as thesensor ID code.

In some situations, it can be desirable to wait an amount of time afterinsertion of the sensor to allow the sensor to equilibrate in vivo, alsoreferred to as “break-in.” Accordingly, the sensor electronics can beconfigured to aid in decreasing the break-in time of the sensor byapplying different voltage settings (for example, starting with a highervoltage setting and then reducing the voltage setting) to speed theequilibration process.

In some situations, the sensor may not properly deploy, connect to, orotherwise operate as intended. Accordingly, the sensor electronics canbe configured such that if the current obtained from the workingelectrode, or the subsequent conversion of the current into digitalcounts, for example, is outside of an acceptable threshold, then thesensor is marked with an error flag, or the like. The error flag can betransmitted to the receiver to instruct the user to reinsert a newsensor, or to implement some other error correction.

The above-described detection and transmission methods can beadvantageously employed to minimize or eliminate human interaction withthe sensor, thereby minimizing human error and/or inconvenience.Additionally, the sensors of preferred embodiments do not require thatthe receiver be in proximity to the transmitter during sensor insertion.Any one or more of the above described methods of detecting andtransmitting insertion of a sensor and/or electronics unit can becombined or modified, as is appreciated by one skilled in the art.

On-Skin Device

FIG. 14B is a perspective view of an alternative embodiment, wherein theelectronics unit and/or mounting unit, hereinafter referred to as the“on-skin device,” is configured to communicate sensor informationdirectly to the user (host). The electronics unit can be detachable fromthe mounting unit in certain embodiments. In other embodiments, theelectronics unit is not detachable from the mounting unit. FIG. 14Bshows an embodiment wherein the electronics unit 16 and mounting unit 14collectively form the on-skin device. The on-skin device furtherincludes a user interface 156, which in the illustrated embodimentincludes a readable screen that displays sensor information; however,other user interface configurations can also be employed.

In some embodiments, the user interface 156 of the on-skin device isconfigured to vibrate or audibly sound in order to attract the attentionof the host, e.g., when a glucose level has risen beyond a setthreshold. Although in the illustrated embodiment, the user interface ofthe on-skin device is configured with an LCD screen, other methods ofdata communication are possible, e.g., computer-generated audibleinformation, tactile signals, or other user interface types. The term“user interface” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to any method of communication to the user. Inembodiments wherein the user interface is a visible display, the displaycan include one or more of: a number representing the analyte value,trend information (e.g., arrows that represent a speed and/or directionof the rising or falling of the analyte levels), a color-metric reading(e.g., green, red, or one or more other colors), a graph that representshistorical and/or present analyte information, and the like. A varietyof displays and/or interface types can be user selectable in someembodiments.

In one alternative embodiment, the on-skin device is configured toprovide a signal, for example, one- two- or three beeps, long- orshort-beeps, or vibrations representative of a certain condition, forexample, one-beep to indicate a glucose level within the target range,two-beeps to indicate a glucose level in the target range that is risingor falling quickly, and three-beeps to indicate a glucose level that isoutside target range. In some embodiments, the signal is responsive to auser's request for information, for example, by pressing a button. Insuch an embodiment, an “info” button is provided (not shown), which isconfigured to provide these signals (or other communication) responsiveto a user activating (pressing) the button.

In these embodiments, the on-skin device preferably houses the sensorelectronics, which provide systems and methods for measuring,processing, and/or displaying of the sensor data. The sensor electronicsgenerally include hardware, firmware, and/or software that enablemeasurement of levels of the analyte via the sensor and that enableaudible, tactile, or visible communication or display of the sensordata. Accordingly, the sensor electronics preferably enable processingof and displaying of sensor data, for example, the sensor electronicsinclude programming for retrospectively and/or prospectively initiatinga calibration, converting sensor data, updating the calibration, and/orevaluating the calibration for the analyte sensor, for example, such asis described in more detail herein with reference to the sensorelectronics and/or receiver electronics.

The electronics can be affixed to a printed circuit board (PCB), or thelike, and can take a variety of forms. For example, the electronics cantake the form of an integrated circuit (IC), such as anApplication-Specific Integrated Circuit (ASIC), a microcontroller, or aprocessor, such as described in more detail herein with reference tosensor electronics and/or receiver electronics. In some embodiments, thesensor electronics comprise a digital filter, for example, an IIR or FIRfilter, configured to smooth the raw data stream from the A/D converter.

In an embodiment wherein the sensor electronics are at least partiallyremovably attached to the on-skin device, a system can be provided toenable docking of the electronics, and thereby downloading and viewingof the sensor data on a remote device, e.g., a sensor receiver, PDA,computer system, docking station, insulin pump, or the like. In one suchembodiment, the on-skin device provides numerical sensor information;however, a user can dock the removable sensor electronics of the on-skindevice onto the remote device to view additional information (e.g.,graphical sensor information). Alternatively, the on-skin device can beused instead of the receiver to store and process all of the necessarydata until a receiver is available for the transfer of data (or enablinga system that does not require a separate receiver). In some alternativeembodiments, the on-skin device communicates with the receiver via acable, radio frequency, optical, inductive coupling, infrared, microwaveor other known methods of data transmission. In one such exemplaryembodiment, the on-skin device is configured to communicate with thereceiver when “requested” by the receiver. For example, when thereceiver is held in close proximity (e.g., within 3 meters) of thedevice, transmission of sensor data can be requested (e.g., using datatransmission methods such as inductive coupling, optical, infrared, orthe like.)

In some alternative embodiments, a user interface is provided with theon-skin device; however, such a user interface is located in a remotesite from the on-skin device (e.g., via wiring). In one such embodiment,the on-skin device is configured to be worn (e.g., adhered) on the skin(e.g., under clothing) of the host and the user interface is configuredto be visible to the user (e.g., worn on clothing or a belt loop, orclipped to the host's clothing). In some embodiments, the user interfaceis a miniature LCD and/or is configured to provide numerical or audiblevalues.

An on-skin device with data communication directly therefrom can provideimproved convenience to the patient (e.g., there is no need for thepatient to keep track of the receiver and maintain it within apredetermined range of the sensor at all times) and increased ease ofuse (e.g., fewer parts for the patient to understand, program, and/orcarry). Additionally, circumstances exist (e.g., on airplanes, whileswimming, etc.) where a patient may not be able to carry a receiver orduring which time certain wireless transmissions may not be permitted;however, with an on-skin user-communicating device, the patient will notbe without critical sensor data.

Additionally, the on-skin device as described in the preferredembodiments is sufficiently miniature so as to enable adhesion of thedevice to a discreet insertion location (e.g., under the user's clothingin certain embodiments). Preferably, the on-skin device has a length ofless than about 40 mm and a width of less than about 20 mm and athickness of less than about 10 mm, and more preferably a length lessthan or equal to about 35 mm and a width less than or equal to about 18mm and a thickness of less than or equal to about 9 mm. The dimensionsassociated with the electronics unit/mounting unit subassembly aredescribed in greater detail elsewhere herein.

Receiver

FIG. 15 is a perspective view of a sensor system, including wirelesscommunication between a sensor and a receiver. Preferably theelectronics unit 16 is wirelessly connected to a receiver 158 via one-or two-way RF transmissions or the like. However, a wired connection isalso contemplated. The receiver 158 provides much of the processing anddisplay of the sensor data, and can be selectively worn and/or removedat the host's convenience. Thus, the sensor system 10 can be discreetlyworn, and the receiver 158, which provides much of the processing anddisplay of the sensor data, can be selectively worn and/or removed atthe host's convenience. Particularly, the receiver 158 includesprogramming for retrospectively and/or prospectively initiating acalibration, converting sensor data, updating the calibration,evaluating received reference and sensor data, and evaluating thecalibration for the analyte sensor, such as described in more detailwith reference to U.S. Publication No. US-2005-0027463-A1.

FIGS. 16A to 16D are schematic views of a receiver in first, second,third, and fourth embodiments, respectively. A receiver 1640 comprisessystems necessary to receive, process, and display sensor data from ananalyte sensor, such as described elsewhere herein. Particularly, thereceiver 1640 can be a pager-sized device, for example, and comprise auser interface that has a plurality of buttons 1642 and a liquid crystaldisplay (LCD) screen 1644, and which can include a backlight. In someembodiments the user interface can also include a keyboard, a speaker,and a vibrator such as described with reference to FIG. 17A.

In some embodiments a user is able to toggle through some or all of thescreens shown in FIGS. 16A to 16D using a toggle button on the receiver.In some embodiments, the user is able to interactively select the typeof output displayed on their user interface. In some embodiments, thesensor output can have alternative configurations.

Receiver Electronics

FIG. 17A is a block diagram that illustrates the configuration of themedical device in one embodiment, including a continuous analyte sensor,a receiver, and an external device. In general, the analyte sensorsystem is any sensor configuration that provides an output signalindicative of a concentration of an analyte (e.g., invasive,minimally-invasive, and/or non-invasive sensors as described above). Theoutput signal is sent to a receiver 158 and received by an input module174, which is described in more detail below. The output signal istypically a raw data stream that is used to provide a useful value ofthe measured analyte concentration to a patient or a doctor, forexample. In some embodiments, the raw data stream can be continuously orperiodically algorithmically smoothed or otherwise modified to diminishoutlying points that do not accurately represent the analyteconcentration, for example due to signal noise or other signalartifacts, such as described in U.S. Pat. No. 6,931,327.

Referring again to FIG. 17A, the receiver 158, which is operativelylinked to the sensor system 10, receives a data stream from the sensorsystem 10 via the input module 174. In one embodiment, the input moduleincludes a quartz crystal operably connected to an RF transceiver (notshown) that together function to receive and synchronize data streamsfrom the sensor system 10. However, the input module 174 can beconfigured in any manner that is capable of receiving data from thesensor. Once received, the input module 174 sends the data stream to aprocessor 176 that processes the data stream, such as is described inmore detail below.

The processor 176 is the central control unit that performs theprocessing, such as storing data, analyzing data streams, calibratinganalyte sensor data, estimating analyte values, comparing estimatedanalyte values with time corresponding measured analyte values,analyzing a variation of estimated analyte values, downloading data, andcontrolling the user interface by providing analyte values, prompts,messages, warnings, alarms, or the like. The processor includes hardwareand software that performs the processing described herein, for exampleflash memory provides permanent or semi-permanent storage of data,storing data such as sensor ID, receiver ID, and programming to processdata streams (for example, programming for performing estimation andother algorithms described elsewhere herein) and random access memory(RAM) stores the system's cache memory and is helpful in dataprocessing.

Preferably, the input module 174 or processor module 176 performs aCyclic Redundancy Check (CRC) to verify data integrity, with or withouta method of recovering the data if there is an error. In someembodiments, error correction techniques such as those that use Hammingcodes or Reed-Solomon encoding/decoding methods are employed to correctfor errors in the data stream. In one alternative embodiment, aniterative decoding technique is employed, wherein the decoding isprocessed iteratively (e.g., in a closed loop) to determine the mostlikely decoded signal. This type of decoding can allow for recovery of asignal that is as low as 0.5 dB above the noise floor, which is incontrast to conventional non-iterative decoding techniques (such asReed-Solomon), which requires approximately 3 dB or about twice thesignal power to recover the same signal (e.g., a turbo code).

An output module 178, which is integral with and/or operativelyconnected with the processor 176, includes programming for generatingoutput based on the data stream received from the sensor system 10 andits processing incurred in the processor 176. In some embodiments,output is generated via a user interface 160.

The user interface 160 comprises a keyboard 162, speaker 164, vibrator166, backlight 168, liquid crystal display (LCD) screen 170, and one ormore buttons 172. The components that comprise the user interface 160include controls to allow interaction of the user with the receiver. Thekeyboard 162 can allow, for example, input of user information abouthimself/herself, such as mealtime, exercise, insulin administration,customized therapy recommendations, and reference analyte values. Thespeaker 164 can produce, for example, audible signals or alerts forconditions such as present and/or estimated hyperglycemic orhypoglycemic conditions in a person with diabetes. The vibrator 166 canprovide, for example, tactile signals or alerts for reasons such asdescribed with reference to the speaker, above. The backlight 168 can beprovided, for example, to aid the user in reading the LCD 170 in lowlight conditions. The LCD 170 can be provided, for example, to providethe user with visual data output, such as is described in U.S.Publication No. US-2005-0203360-A1. FIGS. 17B to 17D illustrate someadditional visual displays that can be provided on the screen 170. Insome embodiments, the LCD is a touch-activated screen, enabling eachselection by a user, for example, from a menu on the screen. The buttons172 can provide for toggle, menu selection, option selection, modeselection, and reset, for example. In some alternative embodiments, amicrophone can be provided to allow for voice-activated control.

In some embodiments, prompts or messages can be displayed on the userinterface to convey information to the user, such as reference outliervalues, requests for reference analyte values, therapy recommendations,deviation of the measured analyte values from the estimated analytevalues, or the like. Additionally, prompts can be displayed to guide theuser through calibration or trouble-shooting of the calibration.

In some embodiments, the receiver and/or a device connected to thereceiver is configured to audibly output the user's analyte value(s),trend information (increasing or decreasing analyte values), and thelike, hereinafter referred to as the audible output module. In someembodiments, the audible output module additionally includes: high andlow blood glucose limits at which the module will audibly output theuser's analyte value and/or trend information; English and non-Englishlanguage versions; and choice of male or female voice. In someembodiments, the audible output is transmitted to an earbud worn by thepatient for use where privacy is required or by a patient who issomewhat audibly impaired. The audible output module can be particularlyadvantageous in applications wherein the user is visually and/or hearingimpaired, or is unable to visually check their receiver due to othercircumstances (e.g., operating a motor vehicle or machinery, engaged ina business meeting or social event, or the like).

Additionally, data output from the output module 178 can provide wiredor wireless, one- or two-way communication between the receiver 158 andan external device 180. The external device 180 can be any device thatwherein interfaces or communicates with the receiver 158. In someembodiments, the external device 180 is a computer, and the receiver 158is able to download historical data for retrospective analysis by thepatient or physician, for example. In some embodiments, the externaldevice 180 is a modem or other telecommunications station, and thereceiver 158 is able to send alerts, warnings, emergency messages, orthe like, via telecommunication lines to another party, such as a doctoror family member. In some embodiments, the external device is a hardwarekey, wherein operative connection of the receiver with the hardware keyenables transmission of a license code or other information to thereceiver. In some embodiments, the external device 180 is an insulinpen, and the receiver 158 is able to communicate therapyrecommendations, such as insulin amount and time to the insulin pen. Insome embodiments, the external device 180 is an insulin pump, and thereceiver 158 is able to communicate therapy recommendations, such asinsulin amount and time to the insulin pump. The external device 180 caninclude other technology or medical devices, for example pacemakers,implanted analyte sensor patches, other infusion devices, telemetrydevices, or the like.

The user interface 160, including keyboard 162, buttons 172, amicrophone (not shown), and the external device 180, can be configuredto allow input of data. Data input can be helpful in obtaininginformation about the patient (for example, meal time, exercise, or thelike), receiving instructions from a physician (for example, customizedtherapy recommendations, targets, or the like), and downloading softwareupdates, for example. Keyboard, buttons, touch-screen, and microphoneare all examples of mechanisms by which a user can input data directlyinto the receiver. A server, personal computer, personal digitalassistant, insulin pump, and insulin pen are examples of externaldevices that can provide useful information to the receiver. Otherdevices internal or external to the sensor that measure other aspects ofa patient's body (for example, temperature sensor, accelerometer, heartrate monitor, oxygen monitor, or the like) can be used to provide inputhelpful in data processing. In one embodiment, the user interface canprompt the patient to select an activity most closely related to theirpresent activity, which can be helpful in linking to an individual'sphysiological patterns, or other data processing. In another embodiment,a temperature sensor and/or heart rate monitor can provide informationhelpful in linking activity, metabolism, and glucose excursions of anindividual. While a few examples of data input have been provided here,a variety of information can be input, which can be helpful in dataprocessing.

FIG. 17B is an illustration of an LCD screen 170 showing continuous andsingle point glucose information in the form of a trend graph 184 and asingle numerical value 186. The trend graph shows upper and lowerboundaries 182 representing a target range between which the host shouldmaintain his/her glucose values. Preferably, the receiver is configuredsuch that these boundaries 182 can be configured or customized by auser, such as the host or a care provider. By providing visualboundaries 182, in combination with continuous analyte values over time(e.g., a trend graph 184), a user can better learn how to controlhis/her analyte concentration (e.g., a person with diabetes can betterlearn how to control his/her glucose concentration) as compared tosingle point (single numerical value 186) alone. Although FIG. 17Billustrates a 1 hour trend graph (e.g., depicted with a time range 188of 1 hour), a variety of time ranges can be represented on the screen170, for example, 3 hour, 9 hour, 1 day, and the like.

FIG. 17C is an illustration of an LCD screen 170 showing a low alertscreen that can be displayed responsive to a host's analyteconcentration falling below a lower boundary (see boundaries 182). Inthis exemplary screen, a host's glucose concentration has fallen to 55mg/dL, which is below the lower boundary set in FIG. 17B, for example.The arrow 190 represents the direction of the analyte trend, forexample, indicating that the glucose concentration is continuing todrop. The annotation 192 (“LOW”) is helpful in immediately and clearlyalerting the host that his/her glucose concentration has dropped below apreset limit, and what may be considered to be a clinically safe value,for example. FIG. 17D is an illustration of an LCD screen 170 showing ahigh alert screen that can be displayed responsive to a host's analyteconcentration rising above an upper boundary (see boundaries 182). Inthis exemplary screen, a host's glucose concentration has risen to 200mg/dL, which is above a boundary set by the host, thereby triggering thehigh alert screen. The arrow 190 represents the direction of the analytetrend, for example, indicating that the glucose concentration iscontinuing to rise. The annotation 192 (“HIGH”) is helpful inimmediately and clearly alerting the host that his/her glucoseconcentration has above a preset limit, and what may be considered to bea clinically safe value, for example.

Although a few exemplary screens are depicted herein, a variety ofscreens can be provided for illustrating any of the informationdescribed in the preferred embodiments, as well as additionalinformation. A user can toggle between these screens (e.g., usingbuttons 172) and/or the screens can be automatically displayedresponsive to programming within the receiver 158, and can besimultaneously accompanied by another type of alert (audible or tactile,for example).

In some embodiments the receiver 158 can have a length of from about 8cm to about 15 cm, a width of from about 3.5 cm to about 10 cm, and/or athickness of from about 1 cm to about 3.5 cm. In some embodiments thereceiver 158 can have a volume of from about 120 cm³ to about 180 cm³,and can have a weight of from about 70 g to 130 g. The dimensions andvolume can be higher or lower, depending, e.g., on the type of devicesintegrated (e.g., finger stick devices, pumps, PDAs, and the like.), thetype of user interface employed, and the like.

In some embodiments, the receiver 158 is an application-specific device.In some embodiments the receiver 158 can be a device used for otherfunctions, such as are described in U.S. Pat. No. 6,558,320. Forexample, the receiver 158 can be integrated into a personal computer(PC), a personal digital assistant (PDA), a cell phone, or another fixedor portable computing device. The integration of the receiver 158function into a more general purpose device can comprise the addition ofsoftware and/or hardware to the device. Communication between the sensorelectronics 16 and the receiver 158 function of the more general purposedevice can be implemented with wired or wireless technologies. Forexample, a PDA can be configured with a data communications port and/ora wireless receiver. After the user establishes a communication linkbetween the electronics unit 16 and the PDA, the electronics unit 16transmits data to the PDA which then processes the data according tosoftware which has been loaded thereon so as to display.

Algorithms

FIG. 18A provides a flow chart 200 that illustrates the initialcalibration and data output of the sensor data in one embodiment,wherein calibration is responsive to reference analyte data. Initialcalibration, also referred to as start-up mode, occurs at theinitialization of a sensor, for example, the first time an electronicsunit is used with a particular sensor. In certain embodiments, start-upcalibration is triggered when the system determines that it can nolonger remain in normal or suspended mode, which is described in moredetail with reference to FIG. 21.

Calibration of an analyte sensor comprises data processing that convertssensor data signal into an estimated analyte measurement that ismeaningful to a user. Accordingly, a reference analyte value is used tocalibrate the data signal from the analyte sensor.

At block 202, a sensor data receiving module, also referred to as thesensor data module, receives sensor data (e.g., a data stream),including one or more time-spaced sensor data points, from the sensor 32via the receiver 158, which can be in wired or wireless communicationwith the sensor 32. The sensor data point(s) can be smoothed (filtered)in certain embodiments using a filter, for example, a finite impulseresponse (FIR) or infinite impulse response (IIR) filter. During theinitialization of the sensor, prior to initial calibration, the receiverreceives and stores the sensor data, however it can be configured to notdisplay any data to the user until initial calibration and, optionally,stabilization of the sensor has been established. In some embodiments,the data stream can be evaluated to determine sensor break-in(equilibration of the sensor in vitro or in vivo).

At block 204, a reference data receiving module, also referred to as thereference input module, receives reference data from a reference analytemonitor, including one or more reference data points. In one embodiment,the reference analyte points can comprise results from a self-monitoredblood analyte test (e.g., finger stick test). For example, the user canadminister a self-monitored blood analyte test to obtain an analytevalue (e.g., point) using any known analyte sensor, and then enter thenumeric analyte value into the computer system. Alternatively, aself-monitored blood analyte test is transferred into the computersystem through a wired or wireless connection to the receiver (e.g.computer system) so that the user simply initiates a connection betweenthe two devices, and the reference analyte data is passed or downloadedbetween the self-monitored blood analyte test and the receiver.

In yet another embodiment, the self-monitored analyte monitor (e.g.,SMBG) is integral with the receiver so that the user simply provides ablood sample to the receiver, and the receiver runs the analyte test todetermine a reference analyte value, such as is described in more detailherein and with reference to U.S. Publication No. US-2005-0154271-A1which describes some systems and methods for integrating a referenceanalyte monitor into a receiver for a continuous analyte sensor.

In some embodiments, the integrated receiver comprises a microprocessorwhich can be programmed to process sensor data to perform thecalibration. Such programming, which is stored in a computer readablememory, can also comprise data acceptability testing using criteria suchas that discussed above with reference to FIG. 18A. For example themicroprocessor can be programmed so as to determine the rate of changeof glucose concentration based on the continuous sensor data, andperform calibration only if the rate of change is below a predeterminedthreshold, such as 2 mg/dL/min. In some embodiments the receiver canalso comprise modules to perform a calibration procedure such as isdescribed herein. Such modules include, but are not limited to an inputmodule, a data matching module, a calibration module, a conversionfunction module, a sensor data transformation module, a calibrationevaluation module, a clinical module, a stability module, and a userinterface, each of which have been described herein.

The monitor can be of any suitable configuration. For example, in oneembodiment, the reference analyte points can comprise results from aself-monitored blood analyte test (e.g., from a finger stick test), suchas those described in U.S. Pat. Nos. 6,045,567; 6,156,051; 6,197,040;6,284,125; 6,413,410; and 6,733,655. In one such embodiment, the usercan administer a self-monitored blood analyte test to obtain an analytevalue (e.g., point) using any suitable analyte sensor, and then enterthe numeric analyte value into the computer system (e.g., the receiver).In another such embodiment, a self-monitored blood analyte testcomprises a wired or wireless connection to the receiver (e.g. computersystem) so that the user simply initiates a connection between the twodevices, and the reference analyte data is passed or downloaded betweenthe self-monitored blood analyte test and the receiver. In yet anothersuch embodiment, the self-monitored analyte test is integral with thereceiver so that the user simply provides a blood sample to thereceiver, and the receiver runs the analyte test to determine areference analyte value.

The monitor can be of another configuration, for example, such asdescribed in U.S. Pat. No. 4,994,167, U.S. Pat. No. 4,757,022, U.S. Pat.No. 6,551,494. In alternative embodiments, the single point glucosemonitor of this modular embodiment can be configured as described withreference to U.S. Publication No. US-2005-0154271-A1. In yet alternativeembodiments, the monitor (e.g., integrated receiver) can be configuredusing other glucose meter configurations, for example, such as describedin U.S. Pat. No. 6,641,533 to Causey III, et al. Numerous advantagesassociated with the integrated receiver, such as ensuring accurate timestamping of the single point glucose test at the receiver and otheradvantages described herein, can be provided by an integrated continuousglucose receiver and single point glucose monitor, such as describedherein.

In some alternative embodiments, the reference data is based on sensordata from another substantially continuous analyte sensor, e.g., atranscutaneous analyte sensor described herein, or another type ofsuitable continuous analyte sensor. In an embodiment employing a seriesof two or more transcutaneous (or other continuous) sensors, the sensorscan be employed so that they provide sensor data in discrete oroverlapping periods. In such embodiments, the sensor data from onecontinuous sensor can be used to calibrate another continuous sensor, orbe used to confirm the validity of a subsequently employed continuoussensor.

In some embodiments, reference data can be subjected to “outlierdetection” wherein the accuracy of a received reference analyte data isevaluated as compared to time-corresponding sensor data. In oneembodiment, the reference data is compared to the sensor data on amodified Clarke Error Grid (e.g., a test similar to the Clarke ErrorGrid except the boundaries between the different regions are modifiedslightly) to determine if the data falls within a predeterminedthreshold. If the data is not within the predetermined threshold, thenthe receiver can be configured to request additional reference analytedata. If the additional reference analyte data confirms (e.g., closelycorrelates to) the first reference analyte data, then the first andsecond reference values are assumed to be accurate and calibration ofthe sensor is adjusted or re-initialized. Alternatively, if the secondreference analyte value falls within the predetermined threshold, thenthe first reference analyte value is assumed to be an outlier and thesecond reference analyte value is used by the algorithm(s) instead. Inone alternative embodiments of outlier detection, projection is used toestimate an expected analyte value, which is compared with the actualvalue and a delta evaluated for substantial correspondence. However,other methods of outlier detection are possible.

Certain acceptability parameters can be set for reference valuesreceived from the user. In some embodiments, the calibration processmonitors the continuous analyte sensor data stream to determine apreferred time for capturing reference analyte concentration values forcalibration of the continuous sensor data stream. In an example whereinthe analyte sensor is a continuous glucose sensor, when data (forexample, observed from the data stream) changes too rapidly, thereference glucose value may not be sufficiently reliable for calibrationdue to unstable glucose changes in the host. In contrast, when sensorglucose data are relatively stable (for example, relatively low rate ofchange), a reference glucose value can be taken for a reliablecalibration. For example, in one embodiment, the receiver can beconfigured to only accept reference analyte values of from about 40mg/dL to about 400 mg/dL. As another example, the receiver can beconfigured to only accept reference analyte values when the rate ofchange is less than a predetermined maximum, such as 1, 1.5, 2, 2.5, 3,or 3.5, mg/dL/min. As yet another example, the receiver can beconfigured to only accept reference analyte values when the rate ofacceleration (or deceleration) is less than a predetermined maximum,such as 0.01 mg/dL/min², 0.02 mg/dL/min², 0.03 mg/dL/min², 0.04mg/dL/min², or 0.05 mg/dL/min or more.

In some embodiments, the reference data is pre-screened according toenvironmental and/or physiological issues, such as time of day, oxygenconcentration, postural effects, and patient-entered environmental data.In one example embodiment, wherein the sensor comprises an implantableglucose sensor, an oxygen sensor within the glucose sensor is used todetermine if sufficient oxygen is being provided to successfullycomplete the necessary enzyme and electrochemical reactions for glucosesensing. In another example wherein the sensor comprises an implantableglucose sensor, the counter electrode could be monitored for a“rail-effect,” that is, when insufficient oxygen is provided at thecounter electrode causing the counter electrode to reach operational(e.g., circuitry) limits. In some embodiments the receiver is configuredsuch that when conditions for accepting reference analyte values are notmet, the user is notified. Such notice can include an indication as tothe cause of the unacceptability, such as low oxygen or high rate ofanalyte value change. In some embodiments the indication can alsoinclude an indication of suggested corrective action, such as moderatelyincreasing muscular activity so as to increase oxygen levels or to waituntil the rate of analyte value change reduces to an acceptable value.

In one embodiment, the calibration process can prompt the user via theuser interface to “calibrate now” when the reference analyte values areconsidered acceptable. In some embodiments, the calibration process canprompt the user via the user interface to obtain a reference analytevalue for calibration at intervals, for example when analyteconcentrations are at high and/or low values. In some additionalembodiments, the user interface can prompt the user to obtain areference analyte value for calibration based at least in part uponcertain events, such as meals, exercise, large excursions in analytelevels, faulty or interrupted data readings, or the like. In someembodiments, the algorithms can provide information useful indetermining when to request a reference analyte value. For example, whenanalyte values indicate approaching clinical risk, the user interfacecan prompt the user to obtain a reference analyte value.

In yet another example embodiment, the patient is prompted to enter datainto the user interface, such as meal times and/or amount of exercise,which can be used to determine likelihood of acceptable reference data.Evaluation data, such as described in the paragraphs above, can be usedto evaluate an optimum time for reference analyte measurement.Correspondingly, the user interface can then prompt the user to providea reference data point for calibration within a given time period.Consequently, because the receiver proactively prompts the user duringoptimum calibration times, the likelihood of error due to environmentaland physiological limitations can decrease and consistency andacceptability of the calibration can increase.

At block 206, a data matching module, also referred to as the processormodule, matches reference data (e.g., one or more reference analyte datapoints) with substantially time corresponding sensor data (e.g., one ormore sensor data points) to provide one or more matched data pairs. Onereference data point can be matched to one time corresponding sensordata point to form a matched data pair. Alternatively, a plurality ofreference data points can be averaged (e.g., equally or non-equallyweighted average, mean-value, median, or the like) and matched to onetime corresponding sensor data point to form a matched data pair, onereference data point can be matched to a plurality of time correspondingsensor data points averaged to form a matched data pair, or a pluralityof reference data points can be averaged and matched to a plurality oftime corresponding sensor data points averaged to form a matched datapair.

In one embodiment, time corresponding sensor data comprises one or moresensor data points that occur from about 0 minutes to about 20 minutesafter the reference analyte data time stamp (e.g., the time that thereference analyte data is obtained). In one embodiment, a 5-minute timedelay is chosen to compensate for a system time-lag (e.g., the timenecessary for the analyte to diffusion through a membrane(s) of ananalyte sensor). In alternative embodiments, the time correspondingsensor value can be greater than or less than that of theabove-described embodiment, for example ±60 minutes. Variability in timecorrespondence of sensor and reference data can be attributed to, forexample, a longer or shorter time delay introduced by the data smoothingfilter, or if the configuration of the analyte sensor incurs a greateror lesser physiological time lag.

In some implementations of the sensor, the reference analyte data isobtained at a time that is different from the time that the data isinput into the receiver. Accordingly, the “time stamp” of the referenceanalyte (e.g., the time at which the reference analyte value wasobtained) is not the same as the time at which the receiver obtained thereference analyte data. Therefore, some embodiments include a time stamprequirement that ensures that the receiver stores the accurate timestamp for each reference analyte value, that is, the time at which thereference value was actually obtained from the user.

In certain embodiments, tests are used to evaluate the best-matched pairusing a reference data point against individual sensor values over apredetermined time period (e.g., about 30 minutes). In one suchembodiment, the reference data point is matched with sensor data pointsat 5-minute intervals and each matched pair is evaluated. The matchedpair with the best correlation can be selected as the matched pair fordata processing. In some alternative embodiments, matching a referencedata point with an average of a plurality of sensor data points over apredetermined time period can be used to form a matched pair.

In certain embodiments, the data matching module only forms matchedpairs when a certain analyte value condition is satisfied. Such acondition can include any of the conditions discussed above withreference to embodiments pre-screening or conditionally acceptingreference analyte value data at block 204.

At block 208, a calibration set module, also referred to as thecalibration module or processor module, forms an initial calibration setfrom a set of one or more matched data pairs, which are used todetermine the relationship between the reference analyte data and thesensor analyte data. The matched data pairs, which make up the initialcalibration set, can be selected according to predetermined criteria.The criteria for the initial calibration set can be the same as, ordifferent from, the criteria for the updated calibration sets. Incertain embodiments, the number (n) of data pair(s) selected for theinitial calibration set is one. In other embodiments, n data pairs areselected for the initial calibration set wherein n is a function of thefrequency of the received reference data points. In various embodiments,two data pairs make up the initial calibration set or six data pairsmake up the initial calibration set. In an embodiment wherein asubstantially continuous analyte sensor provides reference data,numerous data points are used to provide reference data from more than 6data pairs (e.g., dozens or even hundreds of data pairs). In oneexemplary embodiment, a substantially continuous analyte sensor provides288 reference data points per day (every five minutes for twenty-fourhours), thereby providing an opportunity for a matched data pair 288times per day, for example. While specific numbers of matched data pairsare referred to in the preferred embodiments, any suitable number ofmatched data pairs per a given time period can be employed.

In certain embodiments, the data pairs are selected only when a certainanalyte value condition is satisfied. Such a condition can include anyof the conditions discussed above with reference to embodimentspre-screening or conditionally accepting reference analyte value data atblock 204. In certain embodiments, the data pairs that form the initialcalibration set are selected according to their time stamp, for example,by waiting a predetermined “break-in” time period after implantation,the stability of the sensor data can be increased. In certainembodiments, the data pairs that form the initial calibration set arespread out over a predetermined time period, for example, a period oftwo hours or more. In certain embodiments, the data pairs that form theinitial calibration set are spread out over a predetermined glucoserange, for example, spread out over a range of at least 90 mg/dL ormore.

At block 210, a conversion function module, also referred to as theconversion module or processor module, uses the calibration set tocreate a conversion function. The conversion function substantiallydefines the relationship between the reference analyte data and theanalyte sensor data.

A variety of known methods can be used with the preferred embodiments tocreate the conversion function from the calibration set. In oneembodiment, wherein a plurality of matched data points form thecalibration set, a linear least squares regression is used to calculatethe conversion function; for example, this regression calculates a slopeand an offset using the equation y=mx+b. A variety of regression orother conversion schemes can be implemented herein.

In certain embodiments, the conversion function module only creates aconversion function when a certain analyte value condition is satisfied.Such a condition can include any of the conditions discussed above withreference to embodiments pre-screening or conditionally acceptingreference analyte value data at block 204 or with reference to selectingdata pairs at block 208.

In some alternative embodiments, the sensor is calibrated with asingle-point through the use of a dual-electrode system to simplifysensor calibration. In one such dual-electrode system, a first electrodefunctions as a hydrogen peroxide sensor including a membrane systemcontaining glucose-oxidase disposed thereon, which operates as describedherein. A second electrode is a hydrogen peroxide sensor that isconfigured similar to the first electrode, but with a modified membranesystem (with the enzyme domain removed, for example). This secondelectrode provides a signal composed mostly of the baseline signal, b.

In some dual-electrode systems, the baseline signal is (electronicallyor digitally) subtracted from the glucose signal to obtain a glucosesignal substantially without baseline. Accordingly, calibration of theresultant difference signal can be performed by solving the equationy=mx with a single paired measurement. Calibration of the implantedsensor in this alternative embodiment can be made less dependent on thevalues/range of the paired measurements, less sensitive to error inmanual blood glucose measurements, and can facilitate the sensor's useas a primary source of glucose information for the user. U.S.Publication No. US-2005-0143635-A1 describes systems and methods forsubtracting the baseline from a sensor signal.

In some alternative dual-electrode system embodiments, the analytesensor is configured to transmit signals obtained from each electrodeseparately (e.g., without subtraction of the baseline signal). In thisway, the receiver can process these signals to determine additionalinformation about the sensor and/or analyte concentration. For example,by comparing the signals from the first and second electrodes, changesin baseline and/or sensitivity can be detected and/or measured and usedto update calibration (e.g., without the use of a reference analytevalue). In one such example, by monitoring the corresponding first andsecond signals over time, an amount of signal contributed by baselinecan be measured. In another such example, by comparing fluctuations inthe correlating signals over time, changes in sensitivity can bedetected and/or measured.

In some alternative embodiments, a regression equation y=m×+b is used tocalculate the conversion function; however, prior information can beprovided for m and/or b, thereby enabling calibration to occur withfewer paired measurements. In one calibration technique, priorinformation (e.g., obtained from in vivo or in vitro tests) determines asensitivity of the sensor and/or the baseline signal of the sensor byanalyzing sensor data from measurements taken by the sensor (e.g., priorto inserting the sensor). For example, if there exists a predictiverelationship between in vitro sensor parameters and in vivo parameters,then this information can be used by the calibration procedure. Forexample, if a predictive relationship exists between in vitrosensitivity and in vivo sensitivity, m≈f(m_(in vitro)), then thepredicted m can be used, along with a single matched pair, to solve forb (b=y−mx). If, in addition, b can be assumed=0, for example with adual-electrode configuration that enables subtraction of the baselinefrom the signal such as described above, then both m and b are known apriori, matched pairs are not needed for calibration, and the sensor canbe completely calibrated e.g. without the need for reference analytevalues (e.g. values obtained after implantation in vivo.)

In another alternative embodiment, prior information can be provided toguide or validate the baseline (b) and/or sensitivity (m) determinedfrom the regression analysis. In this embodiment, boundaries can be setfor the regression line that defines the conversion function such thatworking sensors are calibrated accurately and easily (with two points),and non-working sensors are prevented from being calibrated. If theboundaries are drawn too tightly, a working sensor may not enter intocalibration. Likewise, if the boundaries are drawn too loosely, thescheme can result in inaccurate calibration or can permit non-workingsensors to enter into calibration. For example, subsequent to performingregression, the resulting slope and/or baseline are tested to determinewhether they fall within a predetermined acceptable threshold(boundaries). These predetermined acceptable boundaries can be obtainedfrom in vivo or in vitro tests (e.g., by a retrospective analysis ofsensor sensitivities and/or baselines collected from a set ofsensors/patients, assuming that the set is representative of futuredata).

If the slope and/or baseline fall within the predetermined acceptableboundaries, then the regression is considered acceptable and processingcontinues to the next step (e.g., block 212). Alternatively, if theslope and/or baseline fall outside the predetermined acceptableboundaries, steps can be taken to either correct the regression orfail-safe such that a system will not process or display errant data.This can be useful in situations wherein regression results in errantslope or baseline values. For example, when points (matched pairs) usedfor regression are too close in value, the resulting regressionstatistically is less accurate than when the values are spread fartherapart. As another example, a sensor that is not properly deployed or isdamaged during deployment can yield a skewed or errant baseline signal.

In some alternative embodiments, the sensor system does not requireinitial and/or update calibration by the host; in these alternativeembodiments, also referred to as “zero-point calibration” embodiments,use of the sensor system without requiring a reference analytemeasurement for initial and/or update calibration is enabled. Ingeneral, the systems and methods of the preferred embodiments providefor stable and repeatable sensor manufacture, particularly when tightlycontrolled manufacturing processes are utilized. Namely, a batch ofsensors of the preferred embodiments can be designed with substantiallythe same baseline (b) and/or sensitivity (m) (+/−10%) when tested invitro. Additionally, the sensor of the preferred embodiments can bedesigned for repeatable m and b in vivo. Thus, an initial calibrationfactor (conversion function) can be programmed into the sensor (sensorelectronics and/or receiver electronics) that enables conversion of rawsensor data into calibrated sensor data solely using informationobtained prior to implantation (namely, initial calibration does notrequire a reference analyte value). Additionally, to obviate the needfor recalibration (update calibration) during the life of the sensor,the sensor is designed to minimize drift of the sensitivity and/orbaseline over time in vivo. Accordingly, the preferred embodiments canbe manufactured for zero point calibration.

FIG. 18B is a graph that illustrates one example of using priorinformation for slope and baseline. The x-axis represents referenceglucose data (blood glucose) from a reference glucose source in mg/dL;the y-axis represents sensor data from a transcutaneous glucose sensorof the preferred embodiments in counts. An upper boundary line 215 is aregression line that represents an upper boundary of “acceptability” inthis example; the lower boundary line 216 is a regression line thatrepresents a lower boundary of “acceptability” in this example. Theboundary lines 215, 216 were obtained from retrospective analysis of invivo sensitivities and baselines of glucose sensors as described in thepreferred embodiments.

A plurality of matched data pairs 217 represents data pairs in acalibration set obtained from a glucose sensor as described in thepreferred embodiments. The matched data pairs are plotted according totheir sensor data and time-corresponding reference glucose data. Aregression line 218 represents the result of regressing the matched datapairs 217 using least squares regression. In this example, theregression line falls within the upper and lower boundaries 215, 216indicating that the sensor calibration is acceptable.

However, if the slope and/or baseline had fallen outside thepredetermined acceptable boundaries, which would be illustrated in thisgraph by a line that crosses the upper and/or lower boundaries 215, 216,then the system is configured to assume a baseline value and re-run theregression (or a modified version of the regression) with the assumedbaseline, wherein the assumed baseline value is derived from in vivo orin vitro testing. Subsequently, the newly derived slope and baseline areagain tested to determine whether they fall within the predeterminedacceptable boundaries. Similarly, the processing continues in responseto the results of the boundary test. In general, for a set of matchedpairs (e.g., calibration set), regression lines with higher slope(sensitivity) have a lower baseline and regression lines with lowerslope (sensitivity) have a higher baseline. Accordingly, the step ofassuming a baseline and testing against boundaries can be repeated usinga variety of different assumed baselines based on the baseline,sensitivity, in vitro testing, and/or in vivo testing. For example, if aboundary test fails due to high sensitivity, then a higher baseline isassumed and the regression re-run and boundary-tested. It is preferredthat after about two iterations of assuming a baseline and/orsensitivity and running a modified regression, the system assumes anerror has occurred (if the resulting regression lines fall outside theboundaries) and fail-safe. The term “fail-safe” includes modifying thesystem processing and/or display of data responsive to a detected erroravoid reporting of inaccurate or clinically irrelevant analyte values.

In these various embodiments utilizing an additional electrode, priorinformation (e.g., in vitro or in vivo testing), signal processing, orother information for assisting in the calibration process can be usedalone or in combination to reduce or eliminate the dependency of thecalibration on reference analyte values obtained by the host.

At block 212, a sensor data transformation module, also referred to asthe calibration module, conversion module, or processor module, uses theconversion function to transform sensor data into substantiallyreal-time analyte value estimates, also referred to as calibrated data,or converted sensor data, as sensor data is continuously (orintermittently) received from the sensor. For example, the sensor data,which can be provided to the receiver in “counts,” is translated in toestimate analyte value(s) in mg/dL. In other words, the offset value atany given point in time can be subtracted from the raw value (e.g., incounts) and divided by the slope to obtain the estimate analyte value:${{mg}\text{/}{dL}} = \frac{\left( {{rawvalue} - {offset}} \right)}{slope}$

In some alternative embodiments, the sensor and/or reference analytevalues are stored in a database for retrospective analysis.

In certain embodiments, the sensor data transformation module onlyconverts sensor data points into calibrated data points when a certainanalyte value condition is satisfied. Such a condition can include anyof the conditions discussed above with reference to embodimentspre-screening or conditionally accepting reference analyte value data atblock 204, with reference to selecting data pairs at block 208, or withreference to creating a conversion function at block 210.

At block 214, an output module provides output to the user via the userinterface. The output is representative of the estimated analyte value,which is determined by converting the sensor data into a meaningfulanalyte value. User output can be in the form of a numeric estimatedanalyte value, an indication of directional trend of analyteconcentration, and/or a graphical representation of the estimatedanalyte data over a period of time, for example. Other representationsof the estimated analyte values are also possible, for example audio andtactile.

In some embodiments, annotations are provided on the graph; for example,bitmap images are displayed thereon, which represent events experiencedby the host. For example, information about meals, insulin, exercise,sensor insertion, sleep, and the like, can be obtained by the receiver(by user input or receipt of a transmission from another device) anddisplayed on the graphical representation of the host's glucose overtime. It is believed that illustrating a host's life events matched witha host's glucose concentration over time can be helpful in educating thehost to his or her metabolic response to the various events.

In yet another alternative embodiment, the sensor utilizes one or moreadditional electrodes to measure an additional analyte. Suchmeasurements can provide a baseline or sensitivity measurement for usein calibrating the sensor. Furthermore, baseline and/or sensitivitymeasurements can be used to trigger events such as digital filtering ofdata or suspending display of data, all of which are described in moredetail in U.S. Publication No. US-2005-0143635-A1.

FIG. 19A provides a flow chart 220 that illustrates a process which, forexample, a stability module can use in the evaluation of referenceand/or sensor data for stability, and/or for statistical, clinical,and/or physiological acceptability. Although some acceptability testsare disclosed herein, any known statistical, clinical, physiologicalstandards and methodologies can be applied to evaluate the acceptabilityof reference and sensor analyte data.

In some embodiments, a stability determination module is provided, alsoreferred to as the start-up module or processor module, which determinesthe stability of the analyte sensor over a period of time. Some analytesensors can have an initial instability time period during which theanalyte sensor is unstable for environmental, physiological, or otherreasons. Initial sensor instability can occur, for example, when theanalyte sensor is implanted subcutaneously; stabilization of the analytesensor can be dependent upon the maturity of the tissue ingrowth aroundand within the sensor. Initial sensor instability can also occur whenthe analyte sensor is implemented transdermally; stabilization of theanalyte sensor can be dependent upon electrode stabilization and/or thepresence of sweat, for example.

Accordingly, in some embodiments, achieving sensor stability can includewaiting a predetermined time period (e.g., an implantable subcutaneoussensor can require a time period for tissue growth, and a transcutaneoussensor can require time to equilibrate the sensor with the user's skin).In some embodiments, this predetermined waiting period is from about oneminute to about six days, from about 1 day to about five days, or fromabout two days to about four days for a transcutaneous sensor and fromabout 1 day to about six weeks, from about 1 week to about five weeks,or about from two weeks to about four weeks for a subcutaneous sensor.In other embodiments for a transcutaneous sensor the waiting period ispreferably from about 30 minutes to about 24 hours, or more preferablyfrom about one hour to about 12 hours, or from about 2 hours to about 10hours. In some embodiments, the sensitivity (e.g., sensor signalstrength with respect to analyte concentration) can be used to determinethe stability of the sensor; for example, amplitude and/or variabilityof sensor sensitivity can be evaluated to determine the stability of thesensor. In alternative embodiments, detection of pH levels, oxygen,hypochlorite, interfering species (e.g., ascorbate, urea, and/oracetaminophen), correlation between sensor and reference values (e.g.,R-value), baseline drift, and/or offset, and the like can be used todetermine the stability of the sensor. In one exemplary embodiment,wherein the sensor is a glucose sensor, a signal can be provided that isassociated with interfering species (e.g., ascorbate, urea,acetaminophen and/or the like), which can be used to evaluate sensorstability. In another exemplary embodiment, wherein the sensor is aglucose sensor, the counter electrode can be monitored for oxygendeprivation, which can be used to evaluate sensor stability orfunctionality.

In some embodiments, the system (e.g., microprocessor) determineswhether the analyte sensor is sufficiently stable according to certaincriteria, such as are described above with reference to FIG. 18A. In oneembodiment wherein the sensor is an implantable glucose sensor, thesystem waits a predetermined time period for sufficient tissue ingrowthand evaluates the sensor sensitivity (e.g., from about one minute to sixweeks). In another embodiment, the receiver determines sufficientstability based on oxygen concentration near the sensor head. In yetanother embodiment, the sensor determines sufficient stability based ona reassessment of baseline drift and/or offset. In yet anotheralternative embodiment, the system evaluates stability by monitoring thefrequency content of the sensor data stream over a predetermined amountof time (e.g., 24 hours); in this alternative embodiment, a template (ortemplates) are provided that reflect acceptable levels of glucosephysiology and are compared with the actual sensor data, wherein apredetermined degree of agreement between the template and the actualsensor data is indicative of sensor stability. A few examples ofdeterminations of sufficient stability are described herein; however, avariety of known tests and parameters can be used to determine sensorstability without departing from the spirit and scope of the preferredembodiments. If the stability is determined to be insufficient,additional sensor data can be repeatedly taken at predeterminedintervals until a sufficient degree of stability is achieved.

In some embodiments, a clinical acceptability evaluation module, alsoreferred to as clinical module, evaluates the clinical acceptability ofnewly received reference data and/or time corresponding sensor data. Insome embodiments clinical acceptability criteria can include any of theconditions discussed above with reference to FIG. 18A as topre-screening or conditionally accepting reference analyte value data.In some embodiments of evaluating clinical acceptability, the rate ofchange of the reference data as compared to previously obtained data isassessed for clinical acceptability. That is, the rate of change andacceleration (or deceleration) of the concentration of many analytes invivo have certain physiological limits within the body. Accordingly, alimit can be set to determine if the new matched pair is within aphysiologically feasible range, indicated by a rate of change from theprevious data that is within known physiological and/or statisticallimits. Similarly, in some embodiments an algorithm that predicts afuture value of an analyte can be used to predict and then compare anactual value to a time corresponding predicted value to determine if theactual value falls within a clinically acceptable range based on thepredictive algorithm, for example.

In one exemplary embodiment, the clinical acceptability evaluationmodule matches the reference data with a substantially timecorresponding converted sensor value, and plots the matched data on aClarke Error Grid. Such a Clarke Error Grid is described in more detailwith reference to FIG. 19B, which is a graph of two data pairs on aClarke Error Grid that illustrates the evaluation of clinicalacceptability in one exemplary embodiment. The Clarke Error Grid can beused by the clinical acceptability evaluation module to evaluate theclinical acceptability of the disparity between a reference glucosevalue and a sensor glucose (e.g., estimated glucose) value, if any, inan embodiment wherein the sensor is a glucose sensor. The x-axisrepresents glucose reference glucose data and the y-axis representsestimated glucose sensor data. Matched data pairs are plottedaccordingly to their reference and sensor values, respectively. In thisembodiment, matched pairs that fall within the A and B regions of theClarke Error Grid are considered clinically acceptable, while matchedpairs that fall within the C, D, and E regions of the Clarke Error Gridare not considered clinically acceptable. Particularly, FIG. 19B shows afirst matched pair 1992 is shown which falls within the A region of theClarke Error Grid, and therefore is considered clinically acceptable. Asecond matched pair 1994 is shown which falls within the C region of theClarke Error Grid, and therefore is not considered clinicallyacceptable.

A variety of other known methods of evaluating clinical acceptabilitycan be utilized. In one alternative embodiment, the Consensus Grid isused to evaluate the clinical acceptability of reference and sensordata. In another alternative embodiment, a mean absolute differencecalculation can be used to evaluate the clinical acceptability of thereference data. In another alternative embodiment, the clinicalacceptability can be evaluated using any relevant clinical acceptabilitytest, such as a known grid (e.g., Clarke Error or Consensus), and caninclude additional parameters such as time of day and/or an increasingor decreasing trend of the analyte concentration. In another alternativeembodiment, a rate of change calculation can be used to evaluateclinical acceptability. In yet another alternative embodiment, whereinthe reference data is received in substantially real time, theconversion function can be used to predict an estimated glucose value ata time corresponding to the time stamp of the reference analyte value(e.g. when there is a time lag of the sensor data such as describedelsewhere herein). Accordingly, a threshold can be set for the predictedestimated glucose value and the reference analyte value disparity, ifany.

The conventional analyte meters (e.g., self-monitored blood analytetests) are known to have a ±20% error in analyte values. Gross errors inanalyte readings are known to occur due to patient error inself-administration of the blood analyte test. For example, if the userhas traces of sugar on his/her finger while obtaining a blood sample fora glucose concentration test, then the measured glucose value is likelyto be much higher than the actual glucose value in the blood.Additionally, it is known that self-monitored analyte tests (e.g., teststrips) are occasionally subject to manufacturing defects.

Another cause for error includes infrequency and time delay that mayoccur if a user does not self-test regularly, or if a user self-testsregularly but does not enter the reference value at the appropriate timeor with the appropriate time stamp. Therefore, it can be advantageous tovalidate the acceptability of reference analyte values prior toaccepting them as valid entries. Accordingly, the receiver evaluates theclinical acceptability of received reference analyte data prior to theiracceptance as a valid reference value.

In one embodiment, the reference analyte data (and/or sensor analytedata) is evaluated with respect to substantially time correspondingsensor data (and/or substantially time corresponding reference analytedata) to determine the clinical acceptability of the reference analyteand/or sensor analyte data. A determination of clinical acceptabilityconsiders a deviation between time corresponding glucose measurements(e.g., data from a glucose sensor and data from a reference glucosemonitor) and the risk (e.g., to the decision making of a diabeticpatient) associated with that deviation based on the glucose valueindicated by the sensor and/or reference data. Evaluating the clinicalacceptability of reference and sensor analyte data, and controlling theuser interface dependent thereon, can minimize clinical risk.

In one embodiment, the receiver evaluates clinical acceptability eachtime reference data is obtained. In another embodiment, the receiverevaluates clinical acceptability after the initial calibration andstabilization of the sensor. In some embodiments, the receiver evaluatesclinical acceptability as an initial pre-screen of reference analytedata, for example after determining if the reference glucose measurementis from about 40 to about 400 mg/dL. In other embodiments, other methodsof pre-screening data can be used, for example by determining if areference analyte data value is physiologically feasible based onprevious reference analyte data values (e.g., below a maximum rate ofchange).

In some embodiments, a calibration evaluation module evaluates the newmatched pair(s) for selective inclusion into the calibration set. Insome embodiments, the receiver simply adds the updated matched data pairinto the calibration set, displaces the oldest and/or least concordantmatched pair from the calibration set, and proceeds to recalculate theconversion function accordingly.

In some embodiments, the calibration evaluation includes evaluating onlythe new matched data pair. In some embodiments, the calibrationevaluation includes evaluating all of the matched data pairs in theexisting calibration set and including the new matched data pair; insuch embodiments not only is the new matched data pair evaluated forinclusion (or exclusion), but additionally each of the data pairs in thecalibration set are individually evaluated for inclusion (or exclusion).In some alternative embodiments, the calibration evaluation includesevaluating all possible combinations of matched data pairs from theexisting calibration set and including the new matched data pair todetermine which combination best meets the inclusion criteria. In someadditional alternative embodiments, the calibration evaluation includesa combination of at least two of the above-described evaluation method.

Inclusion criteria include at least one criterion that defines a set ofmatched data pairs that form a substantially optimal calibration set.Such criteria can include any of the conditions discussed above withreference to FIG. 18A concerning methods of pre-screening orconditionally accepting reference analyte value data. One inclusioncriterion involves the time stamp of the matched data pairs (that makeup the calibration set) spanning at least a predetermined time period(e.g., three hours). Another inclusion criterion involves the timestamps of the matched data pairs not being more than a predetermined age(e.g., one week old). Another inclusion criterion involves the matchedpairs of the calibration set having a substantially evenly distributedamount of high and low raw sensor data, estimated sensor analyte values,and/or reference analyte values. Another criterion involves all rawsensor data, estimated sensor analyte values, and/or reference analytevalues being within a predetermined range (e.g., 40 to 400 mg/dL forglucose values). Another criterion involves a rate of change of theanalyte concentration (e.g., from sensor data) during the time stamp ofthe matched pair(s). For example, sensor and reference data obtainedduring the time when the analyte concentration is undergoing a slow rateof change is typically less susceptible to inaccuracies caused by timelag and other physiological and non-physiological effects. Anothercriterion involves the congruence of respective sensor and referencedata in each matched data pair; the matched pairs with the mostcongruence are chosen. Another criterion involves physiological changes(e.g., low oxygen due to a user's posture that may effect the functionof a subcutaneously implantable analyte sensor) to ascertain alikelihood of error in the sensor value. Evaluation of calibration setcriteria can involve evaluating one, some, or all of the above describedinclusion criteria. It is contemplated that additional embodiments cancomprise additional inclusion criteria not explicitly described herein.

In some embodiments, a quality evaluation module evaluates the qualityof the calibration. In one embodiment, the quality of the calibration isbased on the association of the calibration set data using statisticalanalysis. Statistical analysis can include any known cost function, suchas linear regression, non-linear mapping/regression, rank (e.g.,non-parametric) correlation, least mean square fit, mean absolutedeviation (MAD), mean absolute relative difference, and the like. Theresult of the statistical analysis provides a measure of the associationof data used in calibrating the system. A threshold of data associationcan be set to determine if sufficient quality is exhibited in acalibration set.

In another embodiment, the quality of the calibration is determined byevaluating the calibration set for clinical acceptability, such as, forexample using a Clarke Error Grid, Consensus Grid, or clinicalacceptability test. As an example, the matched data pairs that form thecalibration set can be plotted on a Clarke Error Grid, such that whenall matched data pairs fall within the A and B regions of the ClarkeError Grid, then the calibration is determined to be clinicallyacceptable.

In yet another alternative embodiment, the quality of the calibration isdetermined based initially on the association of the calibration setdata using statistical analysis, and then by evaluating the calibrationset for clinical acceptability. If the calibration set fails thestatistical and/or the clinical test, the calibration processingrecalculates the conversion function with a new (e.g., optimized) set ofmatched data pairs. In this embodiment, the processing loop iteratesuntil the quality evaluation module: 1) determines clinicalacceptability; 2) determines sufficient statistical data association; 3)determines both clinical acceptability and sufficient statistical dataassociation; or 4) surpasses a threshold of iterations.

Calibration of analyte sensors can be variable over time; that is, theconversion function suitable for one point in time may not be suitablefor another point in time (e.g., hours, days, weeks, or months later).For example, in an embodiment wherein the analyte sensor issubcutaneously implantable, the maturation of tissue ingrowth over timecan cause variability in the calibration of the analyte sensor. Asanother example, physiological changes in the user (e.g., metabolism,interfering blood constituents, and lifestyle changes) can causevariability in the calibration of the sensor. Accordingly, acontinuously updating calibration algorithm that includes reforming thecalibration set, and thus recalculating the conversion function, overtime according to a set of inclusion criteria is advantageous.

One cause for discrepancies in reference and sensor data is asensitivity drift that can occur over time, when a sensor is insertedinto a host and cellular invasion of the sensor begins to blocktransport of the analyte to the sensor, for example. Therefore, it canbe advantageous to validate the acceptability of converted sensor dataagainst reference analyte data, to determine if a drift of sensitivityhas occurred and whether the calibration should be updated.

In one embodiment, the reference analyte data is evaluated with respectto substantially time corresponding converted sensor data to determinethe acceptability of the matched pair. For example, clinicalacceptability considers a deviation between time corresponding analytemeasurements (for example, data from a glucose sensor and data from areference glucose monitor) and the risk (for example, to the decisionmaking of a person with diabetes) associated with that deviation basedon the glucose value indicated by the sensor and/or reference data.Evaluating the clinical acceptability of reference and sensor analytedata, and controlling the user interface dependent thereon, can minimizeclinical risk. Preferably, the receiver evaluates clinical acceptabilityeach time reference data is obtained.

After initial calibration, such as is described in more detail withreference to FIG. 18, the sensor data receiving module 222 receivessubstantially continuous sensor data (e.g., a data stream) via areceiver and converts that data into estimated analyte values. As usedherein, the term “substantially continuous” is a broad term and is usedin its ordinary sense, without limitation, to refer to a data stream ofindividual measurements taken at time intervals (e.g., time-spaced)ranging from fractions of a second up to, e.g., 1, 2, or 5 minutes ormore. As sensor data is continuously converted, it can be occasionallyrecalibrated in response to changes in sensor sensitivity (drift), forexample. Initial calibration and re-calibration of the sensor require areference analyte value. Accordingly, the receiver can receive referenceanalyte data at any time for appropriate processing.

At block 222, the reference data receiving module, also referred to asthe reference input module, receives reference analyte data from areference analyte monitor. In one embodiment, the reference datacomprises one analyte value obtained from a reference monitor. In somealternative embodiments however, the reference data includes a set ofanalyte values entered by a user into the interface and averaged byknown methods, such as are described elsewhere herein. In somealternative embodiments, the reference data comprises a plurality ofanalyte values obtained from another continuous analyte sensor.

The reference data can be pre-screened according to environmental andphysiological issues, such as time of day, oxygen concentration,postural effects, and patient-entered environmental data. In oneexemplary embodiment, wherein the sensor comprises an implantableglucose sensor, an oxygen sensor within the glucose sensor is used todetermine if sufficient oxygen is being provided to successfullycomplete the necessary enzyme and electrochemical reactions for accurateglucose sensing. In another exemplary embodiment, the patient isprompted to enter data into the user interface, such as meal timesand/or amount of exercise, which can be used to determine likelihood ofacceptable reference data. In yet another exemplary embodiment, thereference data is matched with time-corresponding sensor data, which isthen evaluated on a modified clinical error grid to determine itsclinical acceptability.

Some evaluation data, such as described in the paragraph above, can beused to evaluate an optimum time for reference analyte measurement.Correspondingly, the user interface can then prompt the user to providea reference data point for calibration within a given time period.Consequently, because the receiver proactively prompts the user duringoptimum calibration times, the likelihood of error due to environmentaland physiological limitations can decrease and consistency andacceptability of the calibration can increase.

At block 224, the evaluation module, also referred to as acceptabilitymodule, evaluates newly received reference data. In one embodiment, theevaluation module evaluates the clinical acceptability of newly receivedreference data and time corresponding converted sensor data (new matcheddata pair). In one embodiment, a clinical acceptability evaluationmodule 224 matches the reference data with a substantially timecorresponding converted sensor value, and determines the Clarke ErrorGrid coordinates. In this embodiment, matched pairs that fall within theA and B regions of the Clarke Error Grid are considered clinicallyacceptable, while matched pairs that fall within the C, D, and E regionsof the Clarke Error Grid are not considered clinically acceptable.

A variety of other known methods of evaluating clinical acceptabilitycan be utilized. In one alternative embodiment, the Consensus Grid isused to evaluate the clinical acceptability of reference and sensordata. In another alternative embodiment, a mean absolute differencecalculation can be used to evaluate the clinical acceptability of thereference data. In another alternative embodiment, the clinicalacceptability can be evaluated using any relevant clinical acceptabilitytest, such as a known grid (e.g., Clarke Error or Consensus), andadditional parameters, such as time of day and/or the increase ordecreasing trend of the analyte concentration. In another alternativeembodiment, a rate of change calculation can be used to evaluateclinical acceptability. In yet another alternative embodiment, whereinthe received reference data is in substantially real time, theconversion function could be used to predict an estimated glucose valueat a time corresponding to the time stamp of the reference analyte value(this can be required due to a time lag of the sensor data such asdescribed elsewhere herein). Accordingly, a threshold can be set for thepredicted estimated glucose value and the reference analyte valuedisparity, if any. In some alternative embodiments, the reference datais evaluated for physiological and/or statistical acceptability asdescribed in more detail elsewhere herein.

At decision block 226, results of the evaluation are assessed. Ifacceptability is determined, then processing continues to block 228 tore-calculate the conversion function using the new matched data pair inthe calibration set.

At block 228, the conversion function module re-creates the conversionfunction using the new matched data pair associated with the newlyreceived reference data. In one embodiment, the conversion functionmodule adds the newly received reference data (e.g., including thematched sensor data) into the calibration set, and recalculates theconversion function accordingly. In alternative embodiments, theconversion function module displaces the oldest, and/or least concordantmatched data pair from the calibration set, and recalculates theconversion function accordingly.

At block 230, the sensor data transformation module uses the newconversion function (from block 228) to continually (or intermittently)convert sensor data into estimated analyte values, also referred to ascalibrated data, or converted sensor data, such as is described in moredetail above.

At block 232, an output module provides output to the user via the userinterface. The output is representative of the estimated analyte value,which is determined by converting the sensor data into a meaningfulanalyte value. User output can be in the form of a numeric estimatedanalyte value, an indication of directional trend of analyteconcentration, and/or a graphical representation of the estimatedanalyte data over a period of time, for example. Other representationsof the estimated analyte values are also possible, for example audio andtactile.

If, however, acceptability is determined at decision block 226 asnegative (unacceptable), then the processing progresses to block 234 toadjust the calibration set. In one embodiment of a calibration setadjustment, the conversion function module removes one or more oldestmatched data pair(s) and recalculates the conversion functionaccordingly. In an alternative embodiment, the conversion functionmodule removes the least concordant matched data pair from thecalibration set, and recalculates the conversion function accordingly.

At block 236, the conversion function module re-creates the conversionfunction using the adjusted calibration set. While not wishing to bebound by theory, it is believed that removing the least concordantand/or oldest matched data pair(s) from the calibration set can reduceor eliminate the effects of sensor sensitivity drift over time,adjusting the conversion function to better represent the currentsensitivity of the sensor.

At block 224, the evaluation module re-evaluates the acceptability ofnewly received reference data with time corresponding converted sensordata that has been converted using the new conversion function (block236). The flow continues to decision block 238 to assess the results ofthe evaluation, such as described with reference to decision block 226,above. If acceptability is determined, then processing continues toblock 230 to convert sensor data using the new conversion function andcontinuously display calibrated sensor data on the user interface.

If, however, acceptability is determined at decision block 226 asnegative, then the processing loops back to block 234 to adjust thecalibration set once again. This process can continue until thecalibration set is no longer sufficient for calibration, for example,when the calibration set includes only one or no matched data pairs withwhich to create a conversion function. In this situation, the system canreturn to the initial calibration or start-up mode, which is describedin more detail with reference to FIGS. 18 and 21, for example.Alternatively, the process can continue until inappropriate matched datapairs have been sufficiently purged and acceptability is positivelydetermined.

In alternative embodiments, the acceptability is determined by a qualityevaluation, for example, calibration quality can be evaluated bydetermining the statistical association of data that forms thecalibration set, which determines the confidence associated with theconversion function used in calibration and conversion of raw sensordata into estimated analyte values. See, e.g., U.S. Publication No.US-2005-0027463-A1.

Alternatively, each matched data pair can be evaluated based on clinicalor statistical acceptability such as described above; however, when amatched data pair does not pass the evaluation criteria, the system canbe configured to ask for another matched data pair from the user. Inthis way, a secondary check can be used to determine whether the erroris more likely due to the reference glucose value or to the sensorvalue. If the second reference glucose value substantially correlates tothe first reference glucose value, it can be presumed that the referenceglucose value is more accurate and the sensor values are errant. Somereasons for errancy of the sensor values include a shift in the baselineof the signal or noise on the signal due to low oxygen, for example. Insuch cases, the system can be configured to re-initiate calibrationusing the secondary reference glucose value. If, however, the referenceglucose values do not substantially correlate, it can be presumed thatthe sensor glucose values are more accurate and the reference glucosevalues eliminated from the algorithm.

FIG. 20 provides is a flow chart 250 that illustrates the evaluation ofcalibrated sensor data for aberrant values in one embodiment. Althoughsensor data are typically accurate and reliable, it can be advantageousto perform a self-diagnostic check of the calibrated sensor data priorto displaying the analyte data on the user interface.

One reason for anomalies in calibrated sensor data includes transientevents, such as local ischemia at the implant site, which cantemporarily cause erroneous readings caused by insufficient oxygen toreact with the analyte. Accordingly, the flow chart 190 illustrates oneself-diagnostic check that can be used to catch erroneous data beforedisplaying it to the user.

At block 252, a sensor data receiving module, also referred to as thesensor data module, receives new sensor data from the sensor.

At block 254, the sensor data transformation module continuously (orintermittently) converts new sensor data into estimated analyte values,also referred to as calibrated data.

At block 256, a self-diagnostic module compares the new calibratedsensor data with previous calibrated sensor data, for example, the mostrecent calibrated sensor data value. In comparing the new and previoussensor data, a variety of parameters can be evaluated. In oneembodiment, the rate of change and/or acceleration (or deceleration) ofchange of various analytes, which have known physiological limits withinthe body, and sensor data can be evaluated accordingly. For example, alimit can be set to determine if the new sensor data is within aphysiologically feasible range, indicated by a rate of change from theprevious data that is within known physiological (and/or statistical)limits. Similarly, any algorithm that predicts a future value of ananalyte can be used to predict and then compare an actual value to atime corresponding predicted value to determine if the actual valuefalls within a statistically and/or clinically acceptable range based onthe predictive algorithm, for example. In certain embodiments,identifying a disparity between predicted and measured analyte data canbe used to identify a shift in signal baseline responsive to anevaluated difference between the predicted data and time-correspondingmeasured data. In some alternative embodiments, a shift in signalbaseline and/or sensitivity can be determined by monitoring a change inthe conversion function; namely, when a conversion function isre-calculated using the equation y=m×+b, a change in the values of m(sensitivity) or b (baseline) above a pre-selected “normal” threshold,can be used to trigger a fail-safe or further diagnostic evaluation.

Although the above-described self-diagnostics are generally employedwith calibrated sensor data, some alternative embodiments arecontemplated that check for aberrancy of consecutive sensor values priorto sensor calibration, for example, on the raw data stream and/or afterfiltering of the raw data stream. In certain embodiments, anintermittent or continuous signal-to-noise measurement can be evaluatedto determine aberrancy of sensor data responsive to a signal-to-noiseratio above a set threshold. In certain embodiments, signal residuals(e.g., by comparing raw and filtered data) can be intermittently orcontinuously analyzed for noise above a set threshold. In certainembodiments, pattern recognition can be used to identify noiseassociated with physiological conditions, such as low oxygen (see, e.g.,U.S. Publication No. US-2005-0043598-A1), or other known signalaberrancies. Accordingly, in these embodiments, the system can beconfigured, in response to aberrancies in the data stream, to triggersignal estimation, adaptively filter the data stream according to theaberrancy, or the like, as described in more detail in the above citedU.S. Publication No. US-2005-0043598-A1.

In another embodiment, reference analyte values are processed todetermine a level of confidence, wherein reference analyte values arecompared to their time-corresponding calibrated sensor values andevaluated for clinical or statistical accuracy. In yet anotheralternative embodiment, new and previous reference analyte data arecompared in place of or in addition to sensor data. In general, thereexist known patterns and limitations of analyte values that can be usedto diagnose certain anomalies in raw or calibrated sensor and/orreference analyte data.

Block 193 describes additional systems and methods that can by utilizedby the self-diagnostics module of the preferred embodiments.

At decision block 258, the system determines whether the comparisonreturned aberrant values. In one embodiment, the slope (rate of change)between the new and previous sensor data is evaluated, wherein valuesgreater than +/−10, 15, 20, 25, or 30% or more change and/or +/−2, 3, 4,5, 6 or more mg/dL/min, more preferably +/−4 mg/dL/min, rate of changeare considered aberrant. In certain embodiments, other knownphysiological parameters can be used to determine aberrant values.However, a variety of comparisons and limitations can be set.

At block 260, if the values are not found to be aberrant, the sensordata transformation module continuously (or intermittently) convertsreceived new sensor data into estimated analyte values, also referred toas calibrated data.

At block 262, if the values are found to be aberrant, the system goesinto a suspended mode, also referred to as fail-safe mode in someembodiments, which is described in more detail below with reference toFIG. 21. In general, suspended mode suspends display of calibratedsensor data and/or insertion of matched data pairs into the calibrationset. Preferably, the system remains in suspended mode until receivedsensor data is not found to be aberrant. In certain embodiments, a timelimit or threshold for suspension is set, after which system and/or userinteraction can be required, for example, requesting additionalreference analyte data, replacement of the electronics unit, and/orreset.

In some alternative embodiments, in response to a positive determinationof aberrant value(s), the system can be configured to estimate one ormore glucose values for the time period during which aberrant valuesexist. Signal estimation generally refers to filtering, data smoothing,augmenting, projecting, and/or other methods for estimating glucosevalues based on historical data, for example. In one implementation ofsignal estimation, physiologically feasible values are calculated basedon the most recent glucose data, and the aberrant values are replacedwith the closest physiologically feasible glucose values. See also U.S.Publication No. US-2005-0027463-A1, U.S. Publication No.US-2005-0043598-A1, and U.S. Publication No. US-2005-0203360-A1.

FIG. 21 provides a flow chart 280 that illustrates a self-diagnostic ofsensor data in one embodiment. Although reference analyte values canuseful for checking and calibrating sensor data, self-diagnosticcapabilities of the sensor provide for a fail-safe for displaying sensordata with confidence and enable minimal user interaction (for example,requiring reference analyte values only as needed).

At block 282, a sensor data receiving module, also referred to as thesensor data module, receives new sensor data from the sensor.

At block 284, the sensor data transformation module continuously (orintermittently) converts received new sensor data into estimated analytevalues, also referred to as calibrated data.

At block 286, a self-diagnostics module, also referred to as a fail-safemodule, performs one or more calculations to determine the accuracy,reliability, and/or clinical acceptability of the sensor data. Someexamples of the self-diagnostics module are described above, withreference block 256. The self-diagnostics module can be furtherconfigured to run periodically (e.g., intermittently or in response to atrigger), for example, on raw data, filtered data, calibrated data,predicted data, and the like.

In certain embodiments, the self-diagnostics module evaluates an amountof time since sensor insertion into the host, wherein a threshold is setfor the sensor's usable life, after which time period the sensor isconsidered to be unreliable. In certain embodiments, theself-diagnostics module counts the number of times a failure or reset isrequired (for example, how many times the system is forced intosuspended or start-up mode), wherein a count threshold is set for apredetermined time period, above which the system is considered to beunreliable. In certain embodiments, the self-diagnostics module comparesnewly received calibrated sensor data with previously calibrated sensordata for aberrant values, such as is described in more detail withreference to FIG. 5, above. In certain embodiments, the self-diagnosticsmodule evaluates clinical acceptability, such as is described in moredetail with reference to FIG. 20, above. In certain embodiments,diagnostics, such as are described in U.S. Publication No.US-2005-0161346-A1 and U.S. Publication No. US-2005-0143635-A1, can beincorporated into the systems of preferred embodiments for systemdiagnosis, for example, for identifying interfering species on thesensor signal and for identifying drifts in baseline and sensitivity ofthe sensor signal.

In some embodiments, an interface control module, also referred to asthe fail-safe module, controls the user interface based upon theclinical acceptability of the reference data received. If the referencedata is not considered clinically acceptable, then a fail-safe modulebegins the initial stages of fail-safe mode. In some embodiments, theinitial stages of fail-safe mode include altering the user interface sothat estimated sensor data is not displayed to the user. In someembodiments, the initial stages of fail-safe mode include prompting theuser to repeat the reference analyte test and provide another referenceanalyte value. The repeated analyte value is then evaluated for clinicalacceptability.

If the results of the repeated analyte test are determined to beclinically unacceptable, then the fail-safe module can alter the userinterface to reflect full fail-safe mode. In one embodiment, fullfail-safe mode includes discontinuing sensor analyte display output onthe user interface. In other embodiments, color-coded information, trendinformation, directional information (e.g., arrows or angled lines),gauges, and/or other fail-safe information can be displayed, forexample.

The initial stages of fail-safe mode and full fail safe mode can includeuser interface control, for example. Additionally, it is contemplatedherein that a variety of different modes between initial and fullfail-safe mode can be provided, depending on the relative quality of thecalibration. In other words, the confidence level of the calibrationquality can control a plurality of different user interface screensproviding error bars, +values, and the like. Similar screens can beimplemented in various clinical acceptability embodiments.

At block 288 of FIG. 21, a mode determination module, which can be apart of the sensor evaluation module 224, determines in which mode thesensor is set (or remains in). In some embodiments, the system isprogrammed with three modes: 1) start-up mode; 2) normal mode; and 3)suspended mode. Although three modes are described herein, the preferredembodiments are not limited to the number or types of modes with whichthe system can be programmed. In some embodiments, the system is definedas “in-cal” (in calibration) in normal mode; otherwise, the system isdefined as “out-of-cal’ (out of calibration) in start-up and suspendedmode. The terms as used herein are meant to describe the functionalityand are not limiting in their definitions.

Preferably, a start-up mode is provided wherein the start-up mode is setwhen the system determines that it can no longer remain in suspended ornormal mode (for example, due to problems detected by theself-diagnostics module, such as described in more detail above) and/orwhen the system is notified that a new sensor has been inserted. Uponinitialization of start-up mode, the system ensures that any old matcheddata pairs and/or calibration information is purged. In start-up mode,the system initializes the calibration set, such as is described in moredetail with reference to FIG. 14, above. Once the calibration set hasbeen initialized, sensor data is ready for conversion and the system isset to normal mode.

Preferably, a normal mode is provided wherein the normal mode is setwhen the system is accurately and reliably converting sensor data, forexample, wherein clinical acceptability is positively determined,aberrant values are negatively determined, and/or the self-diagnosticsmodules confirms reliability of data. In normal mode, the systemcontinuously (or intermittently) converts (or calibrates) sensor data.Additionally, reference analyte values received by the system arematched with sensor data points and added to the calibration set.

In certain embodiments, the calibration set is limited to apredetermined number of matched data pairs, after which the systemspurges old or less desirable matched data pairs when a new matched datapair is added to the calibration set. Less desirable matched data pairscan be determined by inclusion criteria, which include one or morecriteria that define a set of matched data pairs that form asubstantially optimal calibration set.

Unfortunately, some circumstances can exist wherein a system in normalmode is changed to start-up or suspended mode. In general, the system isprogrammed to change to suspended mode when a failure of clinicalacceptability, aberrant value check, and/or other self-diagnosticevaluation is determined, such as described in more detail above, andwherein the system requires further processing to determine whether asystem re-start is required (e.g., start-up mode). In general, thesystem changes to start-up mode when the system is unable to resolveitself in suspended mode and/or when the system detects that a newsensor has been inserted (e.g., via system trigger or user input).

Preferably, a suspended mode is provided wherein the suspended mode isset when a failure of clinical acceptability, aberrant value check,and/or other self-diagnostic evaluation determines unreliability ofsensor data. In certain embodiments, the system enters suspended modewhen a predetermined time period passes without receiving a referenceanalyte value. In suspended mode, the calibration set is not updatedwith new matched data pairs, and sensor data can optionally beconverted, but not displayed on the user interface. The system can bechanged to normal mode upon resolution of a problem (positive evaluationof sensor reliability from the self-diagnostics module, for example).The system can be changed to start-up mode when the system is unable toresolve itself in suspended mode and/or when the system detects a newsensor has been inserted (via system trigger or user input).

The systems of preferred embodiments, including a transcutaneous analytesensor, mounting unit, electronics unit, applicator, and receiver forinserting the sensor, and measuring, processing, and displaying sensordata, provide improved convenience and accuracy because of theirdesigned stability within the host's tissue with minimum invasivetrauma, while providing a discreet and reliable data processing anddisplay, thereby increasing overall host comfort, confidence, safety,and convenience. Namely, the geometric configuration, sizing, andmaterial of the sensor of the preferred embodiments enable themanufacture and use of an atraumatic device for continuous measurementof analytes, in contrast to conventional continuous glucose sensorsavailable to persons with diabetes, for example. Additionally, thesensor systems of preferred embodiments provide a comfortable andreliable system for inserting a sensor and measuring an analyte levelfor up to 30 days or more without surgery. The sensor systems of thepreferred embodiments are designed for host comfort, with chemical andmechanical stability that provides measurement accuracy. Furthermore,the mounting unit is designed with a miniaturized and reusableelectronics unit that maintains a low profile during use. The usablelife of the sensor can be extended by incorporation of a bioactive agentinto the sensor that provides local release of an anti-inflammatory, forexample, in order to slow the subcutaneous foreign body response to thesensor.

After the usable life of the sensor (for example, due to a predeterminedexpiration, potential infection, or level of inflammation), the host canremove the transcutaneous sensor and mounting from the skin, and disposeof the sensor and mounting unit (preferably saving the electronics unitfor reuse). Another transcutaneous sensor system can be inserted withthe reusable electronics unit and thus provide continuous sensor outputfor long periods of time.

EXAMPLES

FIG. 22A is a graphical representation showing transcutaneous glucosesensor data and corresponding blood glucose values over time in a human.The x-axis represents time, the first y-axis represents current inpicoAmps, and the second y-axis represents blood glucose in mg/dL. Asdepicted on the legend, the small diamond points represent the currentmeasured from the working electrode of a transcutaneous glucose sensorof a preferred embodiment; while the larger points represent bloodglucose values of blood withdrawn from a finger stick and analyzed usingan in vitro self-monitoring blood glucose meter (SMBG).

A transcutaneous glucose sensor was built according to the preferredembodiments and implanted in a human host where it remained over aperiod of time. Namely, the sensor was built by providing a platinumwire, vapor-depositing the platinum with Parylene to form an insulatingcoating, helically winding a silver wire around the insulated platinumwire (to form a “twisted pair”), masking sections of the electroactivesurface of the silver wire, vapor-depositing Parylene on the twistedpair, chloridizing the silver electrode to form silver chloridereference electrode, and removing a radial window on the insulatedplatinum wire to expose a circumferential electroactive workingelectrode surface area thereon, this assembly also referred to as a“parylene-coated twisted pair assembly.”

An interference domain was formed on the parylene-coated twisted pairassembly by dip coating in an interference domain solution (7 weightpercent of a 50,000 molecular weight cellulose acetate (Sigma-Aldrich,St. Louis, Mo.) in a 2:1 acetone/ethanol solvent solution), followed bydrying at room temperature for 3 minutes. This interference domainsolution dip coating step was repeated two more times to form aninterference domain comprised of 3 layers of cellulose acetate on theassembly. The dip length (insertion depth) was adjusted to ensure thatthe cellulose acetate covered from the tip of the working electrode,over the exposed electroactive working electrode window, to cover adistal portion of the exposed electroactive reference electrode.

An enzyme domain was formed over the interference domain by subsequentlydip coating the assembly in an enzyme domain solution and drying in avacuum oven for 20 minutes at 50° C. This dip coating process wasrepeated once more to form an enzyme domain having two layers. Aresistance domain was formed over the interference domain bysubsequently spray coating the assembly with a resistance domainsolution and drying the assembly in a vacuum oven for 60 minutes at 50°C. Additionally, the sensors were exposed to electron beam radiation ata dose of 25 kGy, while others (control sensors) were not exposed toelectron beam radiation.

The graph of FIG. 22A illustrates approximately 3 days of data obtainedby the electronics unit operably connected to the sensor implanted inthe human host. Finger-prick blood samples were taken periodically andglucose concentration measured by a blood glucose meter (SMBG). Thegraphs show the subcutaneous sensor data obtained by the transcutaneousglucose sensor tracking glucose concentration as it rose and fell overtime. The time-corresponding blood glucose values show the correlationof the sensor data to the blood glucose data, indicating appropriatetracking of glucose concentration over time.

The raw data signal obtained from the sensor electronics has a currentmeasurement in the picoAmp range. Namely, for every unit (mg/dL) ofglucose, approximately 3.5 pA or less to 7.5 pA or more current ismeasured. Generally, the approximately 3.5 to 7.5 pA/mg/dL sensitivityexhibited by the device can be attributed to a variety of designfactors, including resistance of the membrane system to glucose, amountof enzyme in the membrane system, surface area of the working electrode,and electronic circuitry design. Accordingly, a current in the picoAmprange enables operation of an analyte sensor that: 1) requires (orutilizes) less enzyme (e.g., because the membrane system is highlyresistive and allows less glucose through for reaction in the enzymedomain); 2) requires less oxygen (e.g., because less reaction of glucosein the enzyme domain requires less oxygen as a co-reactant) andtherefore performs better during transient ischemia of the subcutaneoustissue; and 3) accurately measures glucose even in hypoglycemic ranges(e.g., because the electronic circuitry is able to measure very smallamounts of glucose (hydrogen peroxide at the working electrode)).Advantageously, the analyte sensors of the preferred embodiments exhibitimproved performance over convention analyte sensors at least in partbecause a current in the picoAmp range enables operation in conditionsof less enzyme, and less oxygen, better resolution, lower power usage,and therefore better performance in the hypoglycemic range wherein lowermg/dL values conventionally have yielded lower accuracy.

FIG. 22B is a graphical representation showing transcutaneous glucosesensor data and corresponding blood glucose values over time in a human.The x-axis represents time; the y-axis represents glucose concentrationin mg/dL. As depicted on the legend, the small diamond points representthe calibrated glucose data measured from a transcutaneous glucosesensor of a preferred embodiment; while the larger points representblood glucose values of blood withdrawn from a finger stick and analyzedusing an in vitro self-monitoring blood glucose meter (SMBG). Thecalibrated glucose data corresponds to the data of FIG. 22A shown incurrent, except it has been calibrated using algorithms of the preferredembodiments. Accordingly, accurate subcutaneous measurement of glucoseconcentration has been measured and processed using the systems andmethods of the preferred embodiments.

FIG. 23A is a graphical representation showing transcutaneous glucosesensor data and corresponding blood glucose values obtained overapproximately seven days in a human. The x-axis represents time; they-axis represents glucose concentration in mg/dL. As depicted on thelegend, the small diamond points represent the calibrated glucose datameasured from a transcutaneous glucose sensor of a preferred embodiment;while the larger points represent blood glucose values of bloodwithdrawn from a finger stick and analyzed using an in vitroself-monitoring blood glucose meter (SMBG). The calibrated glucose datacorresponds to a sensor that was implanted in a human for approximatelyseven days, showing an extended functional life, as compare to threedays, for example.

Differentiation of Sensor Systems

Some embodiments provide sensor systems suitable for implantation for 1,3, 5, 7, 10, 15, 20, 25, or 30 days or more. Alternatively, sensorsdesigned for shorter or longer durations can have one or more specificdesign features (e.g., membrane systems, bioactive agent(s),architecture, electronic design, power source, software, or the like)customized for the intended sensor life. Similarly, some embodimentsprovide sensor systems suitable for a variety of uses such aspediatrics, adults, geriatrics, persons with type-1 diabetes, personswith type-2 diabetes, intensive care (ICU), hospital use, home use,rugged wear, everyday wear, exercise, and the like, wherein the sensorsystems include particular design features (e.g., membrane systems,bioactive agent(s), architecture, electronic design, power source,software, or the like) customized for an intended use. Accordingly, itcan be advantageous to differentiate sensor systems that aresubstantially similar, for example, sensors wherein the electronics unitof a sensor system can releasably mate with different mounting units, orsensors wherein different electronics units designed for differentfunctionality can mate with a specific mounting unit.

In some embodiments, the mechanical, electrical, and/or software designenables the differentiation (e.g., non-interchangeability) of thesedifferent sensor systems. In other words, the sensor systems can be“keyed” to ensure a proper match between an electronics unit and amounting unit (housing including sensor) as described herein. The terms“key” and “keyed” as used herein are broad terms and are used in theirordinary sense, including, without limitation, to refer to systems andmethods that control the operable connection or operable communicationbetween the sensor, its associated electronics, the receiver, and/or itsassociated electronics. The terms are broad enough to includemechanical, electrical, and software “keys.” For example, a mechanicallydesigned key can include a mechanical design that allows an operableconnection between two parts, for example, a mating between theelectronics unit and the mounting unit wherein the contacts are keyed tomutually engage contacts of complementary parts. As another example, anelectronically designed key can be embedded in a radio frequencyidentification chip (RFID chip) on the mounting unit, wherein theelectronics unit is programmed to identify a predeterminedidentification number (e.g., key) from the RFID chip prior to operableconnection or communication between the sensor and/or sensorelectronics. Alternatively, the sensor's packaging can include an RFIDchip with the key embedded therein and configured to provide keyinformation to the electronics unit and/or receiver. As yet anotherexample, a software key can include a code or serial number thatidentifies a sensor and/or electronics unit.

Accordingly, systems and methods are provided for measuring an analytein a host, including: a sensor configured for transcutaneous insertioninto a host's tissue; a housing adapted for placement external to thehost's tissue and for supporting the sensor; and an electronics unitreleasably attachable to said housing, wherein at least one of thehousing and the electronics unit are keyed to provide a match betweenthe sensor and the electronics unit.

In some embodiments, the housing (including a sensor) and its matchingelectronics unit(s) are keyed by a configuration of the one or morecontacts thereon. FIGS. 4A to 4C illustrate three unique contactconfigurations, wherein the configurations are differentiated by adistance between the first and second contacts located within thehousing. In this embodiment, a properly keyed electronics unit isconfigured with contacts that mate with the contacts on a mating housing(FIGS. 4A to 4C), for example a narrow contact configuration on ahousing mates only with a narrow contact configuration on an electronicsunit. Accordingly, in practice, only an electronics unit comprising acontact configuration that is designed for mutual engagement with asimilarly “keyed” housing can be operably connected thereto.

In some embodiments, the electronics unit is programmed with an ID,hereinafter referred to as a “transmitter ID,” that uniquely identifiesa sensor system. In one exemplary embodiment, wherein a first sensorsystem is designed for 3 day use and a second sensor system is designedfor 7 day use, the transmitter ID can be programmed to begin with a “3”or a “7” in order to differentiate the sensor systems. In practice, a 3day sensor system is programmed for 3 day use (see enforcement of sensorexpiration described in more detail below), and thus upon operableconnection of a 3 day sensor system, the receiver can function for theappropriate duration according to the transmitter ID.

In some embodiments, each sensor system is associated with a unique ornear-unique serial number, which is associated with one or a set ofsensor systems. This serial number can include information such asintended duration, calibration information, and the like, so that uponsensor insertion, and operable connection of the sensor electronics, theserial number can be manually entered into the receiver (from thepackaging, for example) or can be automatically transmitted from thesensor's electronics unit. In this way, the serial number can providethe necessary information to enable the sensor system to function forthe intended duration.

Additionally or alternatively, the electronics unit and/or mounting unitcan be labeled or coded, for example, alpha-numerically, pictorially, orcolorfully, to differentiate unique sensor systems. In this way, a useris less likely to confuse different sensor systems.

Enforcement of Sensor Expiration (Duration of Sensor Life)

In some embodiments, sensor systems are packaged as starter sets, whichinclude at least one reusable (durable) receiver, at least one reusable(durable) electronics unit and one or more single-use sensors, eachincluding an applicator and a mounting unit with the sensor. In somealternative embodiments, the electronics unit is designed for single-useand can optionally be integrally formed with the sensor and/or mountingunit. Preferably, a single receiver, and in some embodiments a singleelectronics unit, is configured for use (e.g., reusable) with aplurality of sensors. Additionally, single-use sensors can be packagedindividually or as sets (e.g., 5, 10, or 15 sensor systems per package(e.g., sensor refill packs)). Preferably, each sensor is configured fora predetermined duration (e.g., 3, 5, 7, 10, 15, 20, 25, or 30 days ormore of operation). In alternative embodiments, the electronics unit canbe configured for single-use; for example, the electronics unit may beintegral with the sensor (e.g., mounting unit with sensor) describedwith this embodiment. Additionally, the applicator can be coupled to themounting unit prior to packaging or configured to be coupled by the userprior to insertion.

Because in some embodiments, the receiver is intended to be reused witha plurality of sensor systems, which sensor systems are configured for apredetermined duration, systems and methods for enforcing the prescribeduse of each sensor system can be advantageous to ensure that the userremoves and reinserts the sensor systems within prescribed time periods.Accordingly, systems and methods are provided for limiting the use ofeach sensor system to its predetermined duration.

In general, transcutaneous sensor systems can be designed for apredetermined (prescribed) amount of time (e.g., a few hours to 30 daysor more). Some embodiments provide sensors suitable for 1, 3, 5, 7, 10,15, 20, 25, or 30 days or more of operation. One potential problem thatcan occur in practice is the continued use of the sensor beyond itsintended life; for example, a host may not remove the sensor after itsintended life and/or the host can detach and reattach the electronicsunit into the mounting unit (which may cause a refresh of the sensorsystem and/or use beyond its intended life in some circumstances).Accordingly, systems and methods are needed for ensuring the sensorsystem is used for its proper duration and that accidental orintentional efforts to improperly extend or reuse the sensor system areavoided.

The preferred embodiments provide systems and methods for measuring ananalyte in a host, the system including: a sensor adapted fortranscutaneous insertion through the skin of a host; a housing adaptedfor placement adjacent to the host's skin and for supporting the sensorupon insertion through the skin; and an electronics unit operablyconnected to the housing, wherein the sensor system is configured toprevent use of the sensor (e.g., to render the sensor inoperative ordisable display of sensor data) beyond a predetermined time period.

In some embodiments, the sensor system is configured to destroy thesensor when the electronics unit is removed and/or after a predeterminedtime period has expired. In one exemplary embodiment, a loop of materialsurrounds a portion of the sensor and is configured to retract thesensor (from the host) when the electronics unit is removed from thehousing. In another embodiment, the sensor system is configured to cut,crimp, or otherwise destroy the sensor when the electronics unit isremoved from the housing.

In some embodiments, the sensor system is programmed to determinewhether to allow an initialization of a new sensor. For example, thereceiver can be programmed to require the sensor be disconnected priorto initiation of the receiver for an additional sensor system. In onesuch exemplary embodiment, the receiver can be programmed to look for azero from the electronics unit, indicating the sensor has beendisconnected, prior to allowing a new sensor to be initiated. This canhelp to ensure that a user actually removes the electronics unit (and/orsensor) prior to initialization of a new sensor. In another suchembodiment, sensor insertion information can be programmed into thesensor electronics, such that the sensor insertion information istransmitted to the receiver to allow initialization of a new sensor.

In some embodiments, the receiver software receives information from theelectronics unit (e.g., intended duration, transmitter ID, expirationdate, serial code, manufacture date, or the like) and is programmed toautomatically shut down after a predetermined time period (intendedduration) or sensor expiration, for example.

In some embodiments, the receiver is programmed to algorithmicallyidentify a new sensor insertion by looking for change in signalcharacteristic (e.g., a spike indicating break-in period, no change insensor count values during the first hour, or the like). If a user hasnot inserted a new sensor, then the continued use of an expired sensorcan be detected and can be used to trigger a shut down of the sensorand/or receiver.

In some embodiments, each sensor system is associated with a unique ornear-unique serial number, which is associated with one or a set ofsensor systems as described in more detail above. In general, the serialnumber can include information such as calibration information, intendedduration, manufacture date, expiration date, and the like. For example,the serial number can provide sensor life (intended duration)information, which can be used to shut down the sensor and/or receiver(e.g., display of sensor data and/or use of the sensor) after theintended sensor life.

In some embodiments, one or a set of sensors are packaged such that aserial number, which is associated with the one sensor and/or the set ofsensors, also referred to as a key or license code, is provided toenable the use of the sensor system. In preferred embodiments, thelicense code includes one or more of the following: a unique number, areceiver ID, a sensor duration, and a number of sensors for which thelicense code is enabled. The unique number preferably includes anauto-generated number that increments each time a license is issued.However, one skilled in the art will appreciate that a variety of uniquenumbering techniques can be utilized; the unique number is designed toreduce or eliminate fraud, such as reuse of a license code. The receiverID (receiver identification) preferably includes a unique numberassociated with an individual receiver, which ensures that the licensecode is used with a particular receiver. The sensor duration preferablyincludes a predetermined time period for which the sensor use isprescribed (e.g., sensor life such as 1, 3, 5, 7, 10, 15, 20, 25, or 30days or more) after which the sensor is disabled. The number of sensorsystems for which the license code is enabled preferably includes anumber that represents how many sensor insertions (e.g., number ofsensor initializations or how many iterations of the sensor duration)are allowed using the unique license code; in some embodiments, this isthe number of sensors provided in a packaged set of sensors.

The license code is designed to be input, either manually orautomatically, into the sensor system (e.g., receiver or on-skindevice), after which the sensor system (e.g., receiver or on-skindevice) controls the display of sensor data. In one embodiment, a useris instructed to obtain a license code and manually enter the code intothe receiver. In one alternative embodiment, a sensor system (e.g.,packaging, single-use portion of the sensor, mounting unit and/orelectronics unit) includes an embedded license code, for example, withinan embedded RFID chip. In one exemplary embodiment, the RFID chip isconfigured to transmit the license code information to the receiver(e.g., when requested by the receiver). In another embodiment, ahardware key is provided with the sensor system (e.g., one or moresensors packaged together), wherein operative connection of the hardwarekey to the receiver transmits a license code from the hardware key tothe receiver.

Preferably, the license code is configured control the amount of timeover which information is obtained from the sensor. The phrase“information . . . obtained from the sensor” can refer withoutlimitation to any sensor information obtained, including measured,processed, transmitted and/or displayed in any manner including:measurement of the analyte information (e.g., glucose concentration) bythe sensor, digitalizing of the sensor information (e.g., raw orfiltered data) by the electronics unit, transmission of the sensorinformation (e.g., sensor data) from the electronics unit, receiving ofthe sensor information by the receiver, storing or processing of thesensor information by the receiver, and/or displaying of the sensorinformation by the receiver or other device. Accordingly, when thelicensed (or prescribed) sensor duration and/or number of sensorinsertions have been met, the receiver is configured to disable the“obtaining of information” (e.g., disabling display of the sensor dataand/or any other method such as described above). In some embodiments,the sensor can continue to collect and store data after the sensorsystem has disabled “obtaining of information.” Additionally oralternatively, the prescribed sensor duration can be enforced using anyof the mechanical (e.g., destruction of the sensor), electrical, orsoftware techniques described elsewhere herein and as will beappreciated by one skilled in the art.

The above described systems and methods for differentiating sensorsystems and enforcing sensor lifetimes can be used alone or incombination, and can be combined with any of the preferred embodiments.

Distributing and Controlling Use of Sensor Systems Including Single-Use(Disposable) and Reusable (Durable) Parts

FIG. 23B is a flow diagram that illustrates a method for distributingand controlling use of sensor systems including disposable and reusableparts 300 in one embodiment.

At block 302, a user (doctor, patient, or other care provider) obtainsreusable sensor system parts. Preferably sensor system is distributedwith a starter pack including at least one of each reusable part. Ingeneral, the reusable sensor parts include at least the receiver,whereby a plurality of single-use sensors can be used with the receiver.In some embodiments the electronics unit is also reusable as shown anddescribed in the illustrated embodiments; however, the sensorelectronics can be integral with the single-use mounting unit/sensor insome embodiments as described elsewhere herein.

At block 304, the user obtains single-use sensor system parts. In someembodiments, the starter pack described above further includes one ormore single-use sensors. Additionally or alternatively, one or aplurality of single-use sensors are packaged together.

At block 306, the user obtains a key, also referred to as a licensecode, configured to enable predefined (prescribed) use of the sensorsystem as described in more detail elsewhere herein. In someembodiments, the key is provided on or in the packaging. In someembodiments, the key is obtained by contacting the distributorelectronically (e.g., via the Internet or e-mail), via telephone,written communication, or other communications protocol. In someembodiments, the key is embedded in a chip (e.g., RFID) on thesingle-use device or packaging. In some embodiments, the license code isprogrammed into a hardware key (e.g., dongle), which is provided withthe sensor system (e.g., package containing one or more sensors).Although a few methods for obtaining a license key are described herein,numerous other methods for providing a key are possible as isappreciated by one skilled in the art.

At block 308, the key is input into the sensor system, for example, intothe receiver. In some embodiments, the key is provided to the user viapaper or other communication from the distributor, the key is inputmanually using buttons on the receiver, for example. In some alternativeembodiments, the key is transmitted from a chip, for example, an RFIDchip embedded in the single-use sensor and/or packaging associated withthe single use device. In some embodiments, operative connection of ahardware key with a port on the receiver enables transmission of thelicense code to the receiver. Other methods for inputting the key arepossible as is appreciated by one skilled in the art.

At block 310, the sensor is inserted into the user, as described in moredetail elsewhere herein and/or as is known in the art. See also U.S.Pat. No. 6,974,437; U.S. Pat. No. 6,892,085; U.S. Pat. No. 6,809,507;U.S. Pat. No. 6,689,056; U.S. Pat. No. 6,666,821; U.S. Pat. No.6,520,326; U.S. Pat. No. 6,512,939; U.S. Pat. No. 6,261,280; U.S. Pat.No. 6,572,542; U.S. Pat. No. 6,284,478; U.S. Pat. No. 6,565,509; U.S.Pat. No. 6,175,752; U.S. Pat. No. 6,329,161; U.S. Pat. No. 6,695,860;and U.S. Pat. No. 6,613,379. In some embodiments, the sensor is insertedinto the host prior to inputting the license code into the receiver.Generally, it is preferred that the user be required to input thelicense code into the sensor system prior to obtaining information(i.e., sensor data) from the sensor.

At block 312, the sensor measures and displays the host's analyte valuesfor the predetermined time period. As described in more detail elsewhereherein, the sensor is generally designed for a particular duration ofuse, for example a 3 day sensor is designed for a duration of 3 days.Some sensors may be designed for longer or shorter durations.

At block 314, the sensor system is disabled. Preferably, the disablingof the sensor includes at least discontinuing the display of sensordata. By discontinuing the display of sensor data, a host will beencouraged to remove the sensor at the appropriate time. However,further mechanical and software designs to disable the use of thedevice, such as destroying the sensor and shutting down all electronicscan also be employed, as are described in more detail elsewhere herein.By utilizing the method of distributing and controlling use of sensorsystems including disposable and reusable parts described herein,patients are more likely to use the sensor systems in a mannerconsistent with physician and/or prescriptive use.

EXAMPLES

The following examples serve to illustrate certain preferred embodimentsand aspects and are not to be construed as limiting the scope thereof.

Transcutaneous Glucose Sensor with Cellulose Acetate Interference Domain

A short term (transcutaneous) sensor was built by providing a platinumwire, vapor-depositing the platinum with Parylene to form an insulatingcoating, helically winding a silver wire around the insulated platinumwire (to form a “twisted pair”), masking sections of electroactivesurface of the silver wire, vapor-depositing Parylene on the twistedpair, chloridizing the silver electrode to form silver chloridereference electrode, and removing a radial window on the insulatedplatinum wire to expose a circumferential electroactive workingelectrode surface area thereon, this assembly also referred to as a“parylene-coated twisted pair assembly.”

An interference domain was formed on the parylene-coated twisted pairassembly by dip coating in an interference domain solution comprising 7weight percent, 50,000 molecular weight cellulose acetate(Sigma-Aldrich, St. Louis, Mo.) in a 2:1 acetone/ethanol solventsolution, followed by drying at room temperature for three minutes. Thisinterference domain solution dip coating step was repeated three moretimes to form an interference domain comprised of four layers ofcellulose acetate on the assembly. The dip length (insertion depth) wasadjusted to ensure that the cellulose acetate covered from the tip ofthe working electrode, over the exposed electroactive working electrodewindow, to cover a distal portion of the exposed electroactive referenceelectrode.

An enzyme domain was formed over the interference domain by subsequentlydip coating the assembly in an enzyme domain solution and drying in avacuum oven for 20 minutes at 50° C. This dip coating process wasrepeated once more to form an enzyme domain comprised of two layers. Aresistance domain was formed over the enzyme domain by subsequentlyspray coating the assembly with a resistance domain solution and driedin a vacuum oven for 60 minutes at 50° C. Both the enzyme domain and theresistance domain were formed as described in more detail in U.S.Publication No. US-2006-0020187-A1.

Additionally, selected sensors (test sensors) were exposed to electronbeam radiation at a dose of 25 kGy, while others (control sensors) werenot exposed to electron beam radiation.

Transcutaneous Glucose Sensor with Cellulose Acetate/Nafion®Interference Domain

Transcutaneous glucose sensors with a cellulose acetate/Nafion®interference domain (CA/Naf sensors) were constructed as described withreference to the transcutaneous glucose sensors with a cellulose acetateinterference domain above; however, after dip coating theparylene-coated twisted pair assembly in the cellulose acetate solution,the cellulose acetate coated assembly was further dip coated in a 5weight percent Nafion® solution in low aliphatic alcohols(Sigma-Aldrich, St. Louis, Mo.) and allowed to dry at room temperaturefor 10 minutes. This Nafion® solution dip coating step was repeatedtwice to form three layers of Nafion® over the cellulose acetate layers.Enzyme and resistance domains were subsequently coated onto thecellulose acetate/Nafion® interference domain coated assembly, andselected test sensors were exposed to electron beam radiation, asdescribed in more detail above.

In Vitro Testing

In vitro tests were run to evaluate the ability of the above-describedsensors to resist uric acid, ascorbic acid, and acetaminophen. Namely,four CA sensors (two before and two after electron beam exposure) wereimmersed in 40, 200, and 400 mg/dL glucose while their electrical signalwas monitored. Subsequently, the sensors were immersed into a solutioncontaining 400 mg/dL glucose plus one of either 0.5 mM uric acid (FIG.24A), 0.23 mM ascorbic acid (FIG. 24B), or 0.22 mM acetaminophen (FIG.24C).

FIG. 24A is a bar graph that illustrates the ability of the CA sensorsto resist uric acid pre- and post-electron beam exposure. The x-axisrepresents the sensors involved in the in vitro testing. Namely, 3CArepresents an interference domain formed on sensors comprised of fourdip coated layers of cellulose acetate as described above. Half of theCA sensors were tested pre-electron beam exposure and half of thesensors were tested post-electron beam exposure as indicated on thelegend. The y-axis represents the percentage amount of signal due to theinterferant (uric acid) as compared to a control sensor (i.e., sensor(s)without an interference domain).

The bar graph shows that in a first set CA sensors (E3), 3% of thecontrol signal was produced by the electron beam treated sensor uponimmersion into the uric acid containing solution (as compared to thecontrol sensor); in contrast, the sensor that was not treated withelectron beam produced an 18% signal increase when immersed in the uricacid containing solution. In a second set of CA sensors (E4), 0.5% ofthe control signal was produced by the electron beam treated sensor uponimmersion into the uric acid containing solution (as compared to thecontrol sensor); in contrast, the sensor that was not treated withelectron beam produced 3% of the control signal when immersed in theuric acid containing solution. Accordingly, it is believed that electronbeam exposure provides improved ability to block uric acid in sensors invitro as compared with sensors that have not been electron beamsterilized.

FIG. 24B is a bar graph that illustrates the ability of the CA sensorsto resist ascorbic acid pre- and post-electron beam exposure. The x-axisrepresents the sensors involved in the in vitro testing. Namely, 3CArepresents an interference domain formed on sensors comprised of fourdip coated layers of cellulose acetate, as described above. Half of thesensors were tested pre-electron beam exposure and half of the sensorswere tested post-electron beam exposure as indicated on the legend. They-axis represents the amount of signal due to the interferant (ascorbicacid) as compared to a control sensor (i.e., sensor(s) without aninterference domain).

The bar graph shows that in a first set CA sensors (E3), 11% of thecontrol signal was produced by the electron beam treated sensor uponimmersion into the ascorbic acid containing solution (as compared to thecontrol sensor); in contrast, the sensor that was not treated withelectron beam produced 39% of the control signal when immersed in theascorbic acid containing solution. In a second set of CA sensors (E4),7% of the control signal was produced by the electron beam treatedsensor upon immersion into the ascorbic acid containing solution (ascompared to the control sensor); in contrast, the sensor that was nottreated with electron beam produced 35% of the control signal whenimmersed in the ascorbic acid containing solution.

FIG. 24C is a bar graph that illustrates the ability of the CA sensorsto resist acetaminophen pre- and post-electron beam exposure. The x-axisrepresents the sensors involved in the in vitro testing. Namely, 3CArepresents an interference domain formed on sensors comprised of fourdip coated layers of cellulose acetate, as described above. Half of thesensors were tested pre-electron beam exposure and half of the sensorswere tested post-electron beam exposure as indicated on the legend. They-axis represents the amount of signal due to the interferant(acetaminophen) as compared to a control sensor (i.e., sensor(s) withoutan interference domain).

The bar graph shows that in a first set CA sensors (E3), 6% of thecontrol signal was produced by the electron beam treated sensor uponimmersion into the acetaminophen containing solution (as compared to thecontrol sensor); in contrast, the sensor that was not treated withelectron beam produced 25% of the control signal when immersed in theacetaminophen containing solution. In a second set of CA sensors (E4),4% of the control signal was produced by the electron beam treatedsensor upon immersion into the acetaminophen containing solution (ascompared to the control sensor); in contrast, the sensor that was nottreated with electron beam produced 20% of the control signal whenimmersed in the acetaminophen containing solution.

While not wishing to be bound by theory, it is believed that treatmentof an interference domain comprising a cellulosic polymer, such ascellulose acetate, by ionizing radiation, such as electron beamradiation, crosslinks the domain and thereby improves the structure ofthe domain and its ability to block interfering species.

In Vivo Testing

FIG. 25A is a graphical representation that shows the results of anexperiment wherein a glucose sensor was implanted in astreptozocin-induced diabetic rat. Particularly, the glucose sensor wasconstructed with a cellulose acetate interference domain and was treatedwith electron beam exposure as described above. The x-axis representstime; the first y-axis represents counts from a raw data stream obtainedfrom the glucose sensor (sensor with CA interference domain); and thesecond y-axis represents blood glucose in mg/dL obtained from tailsticks and measured on a reference self-monitoring blood glucose meter(smbg).

The rat was implanted with the CA sensor and was taken through a glucoseexcursion study on day 1 (see approximately 1 PM to 2 PM). On day 2 ofthe study, the rat was injected in the gut with 75%, 150%, and 225% ofthe maximum therapeutic dose of acetaminophen 0.22 mM (equal toapproximately 0.165, 0.33 and 0.495 mM acetaminophen, respectively) atapproximately 9 AM, 9:30 AM, and 10 AM, respectively as indicated by thearrows on the graph.

The graph illustrates the results of the glucose sensor as compared witha reference blood glucose meter during the glucose and acetaminophentracking studies. During the glucose excursion study on day 1, one cansee that the glucose sensor is indeed tracking glucose as shown by thesensor's increase and subsequent decrease in counts and correspondingsmbg values. Furthermore, during the acetaminophen tracking study, therelative minimal change in sensor value (with corresponding referenceblood glucose meter) indicates the sensor's ability to block signal dueto acetaminophen similar to that of the reference blood glucose meter.Namely, if the sensor had been constructed without an interferencedomain, one would expect to see three step increases in the sensor'ssignal corresponding to the three bolus injections described above.Thus, it is believed that the incorporation of the CA interferencedomain that has been exposed to ionizing beam radiation as describedabove enables the glucose sensor to substantially resist acetaminophenin vivo.

FIG. 25B is a graphical representation that shows the results of anexperiment the wherein a glucose sensor was implanted in astreptozocin-induced diabetic rat. Particularly, the glucose sensor wasconstructed with a cellulose acetate/Nafion® interference domain and wastreated with electron beam exposure as described above. The x-axisrepresents time; the first y-axis represents counts from a raw datastream obtained from the glucose sensor (sensor with CA/Nafion®interference domain); and the second y-axis represents blood glucose inmg/dL obtained from tail sticks and measured on a referenceself-monitoring blood glucose meter (smbg).

The rat was implanted with the CA/Nafion® sensor and was taken through aglucose excursion study on day 1 (see approximately 3 PM to 4 PM). Onday 2 of the study, the rat was injected in the gut with 75%, 150%, and225% of the maximum therapeutic dose of acetaminophen 0.22 mM (equal toapproximately 0.165, 0.33 and 0.495 mM acetaminophen, respectively) atapproximately 11 AM, 11:30 AM, and 12 PM, respectively as indicated bythe arrows on the graph.

The graph illustrates the results of the glucose sensor as compared witha reference blood glucose meter during the glucose and acetaminophentracking studies. During the glucose excursion study on day 1, one cansee that the glucose sensor is indeed tracking glucose as shown by thesensor's increase and subsequent decrease in counts and correspondingsmbg values. Furthermore, during the acetaminophen tracking study, therelatively minimal change in sensor value (with corresponding referenceblood glucose meter) indicates the sensor's ability to block signal dueto acetaminophen similar to that of the reference blood glucose meter.Namely, if the sensor had been constructed without an interferencedomain, one would expect to see three step increases in the sensor'ssignal corresponding to the three bolus injections as shown in FIG. 24C.Thus, it is believed that incorporation of the CA/Nafion® interferencedomain that has been exposed to ionizing radiation as described aboveenables the glucose sensor to substantially resist acetaminophen invivo.

FIG. 25C is a graphical representation that illustrates the lack ofacetaminophen blocking ability of a control glucose sensor without aninterference domain in the study of FIG. 25B. Particularly, the glucosesensor was constructed without an interference domain The x-axisrepresents time; the first y-axis represents counts from a raw datastream obtained from the glucose sensor (without an interferencedomain); and the second y-axis represents blood glucose in mg/dLobtained from tail sticks and measured on a reference self-monitoringblood glucose meter (smbg).

The rat was implanted with the interference domain-free sensor and wastaken through a glucose excursion study on day 1 (see approximately 3 PMto 4 PM). On day 2 of the study, the rat was injected in the gut with75%, 150%, and 225% of the maximum therapeutic dose of acetaminophen0.22 mM (equal to approximately 0.165, 0.33 and 0.495 mM acetaminophen,respectively) at approximately 11 AM, 11:30 AM, and 12 PM, respectivelyas indicated by the arrows on the graph.

The graph illustrates the results of the control glucose sensor ascompared with a reference blood glucose meter during the glucose andacetaminophen tracking studies. During the glucose excursion study onday 1, one can see that the glucose sensor is indeed tracking glucose asshown by the sensor's increase and subsequent decrease in counts andcorresponding smbg values. Furthermore, during the acetaminophentracking study on day 2, three step increases in the sensor's signal canbe seen, which correspond to the three bolus acetaminophen injectionsdescribed above. These three signal increases indicate the affect ofacetaminophen on the sensor signal as compared with correspondingreference blood glucose meter values (smbg) indicates the sensor's lackof ability to block signal due to acetaminophen as compared with that ofthe reference blood glucose meter, for example. Thus, it is believedthat the incorporation of the CA and/or CA/Nafion® interference domainthat has been exposed to ionizing radiation as described above enablesthe glucose sensor to substantially resist acetaminophen in vivo ascompared to a glucose sensor without the interference domain of thepreferred embodiments.

Transcutaneous Glucose Sensor with Cellulose Acetate Interference Domainand PVP Electrode Domain

Transcutaneous glucose sensors with a cellulose acetate (CA)interference domain with and without a PVP electrode domain were eachbuilt as described with reference to the transcutaneous glucose sensorsabove. Namely, a first (control) set of parylene-coated twisted pairassemblies were dip-coated with a CA interference domain and subsequentenzyme and resistance domains as described in more detail. Additionally,a second (test) set of parylene-coated twisted pair assemblies weredip-coated one time with a 10 wt. % PVP (International SpecialtyProducts PVP K-90) solution in DI water, prior to the application of aCA interference domain and subsequent enzyme and resistance domains.

FIG. 26A is a bar graph that represents the break-in time of the testsensors vs. the control sensors. Five test sensors and five controlsensors were built as described above and inserted bi-laterally into arat (each rat receiving one test sensor and one control sensor). Afterinsertion, the sensors measured glucose for a time period at leastbeyond the electrochemical break-in time of each sensor. The data wasanalyzed to determine the electrochemical break-in of each sensor.Electrochemical break-in is well documented and is appreciated by oneskilled in the art, however it can be stated that the time at whichreference glucose data (e.g., from an SMBG meter) substantiallycorrelates with sensor glucose data is an indicator of electrochemicalbreak-in of the sensor. The y-axis represents the amount of timerequired for electrochemical break-in in minutes. The x-axis representsthe 5 rats in this experiment showing the test and control sensors foreach rat. It can be seen from the bar graph that the break-in time ofthe test sensors (with the PVP electrode domain) had faster break-intimes than the control sensors (without PVP electrode domain). Namely,the control sensors had break-in time periods in the range of about 50to about 130 minutes, while the test sensors had break-in time periodsin the range of about 10 to about 40 minutes. Thus, a membrane systemcomprising a cellulosic derivative (e.g., cellulose acetate butyrate)and an electrode domain comprising a hydrophilic polymer (e.g., PVP)enables fast break-in times for a sensor, including not more than about40 minutes, not more than about 30 minutes, preferably not more thanabout 20 minutes, and more preferably not more than about 10 minutes.

Transcutaneous Glucose Sensor with Cellulose Acetate ButyrateInterference Domain

Transcutaneous glucose sensors with a cellulose acetate butyrate (CAB)interference domain were each constructed as described with reference tothe transcutaneous glucose sensors above, namely, by dip-coating aparylene-coated twisted pair assembly with three coats of 17.7 wt. %cellulose acetate butyrate CAB (Eastman Chemical 553-0.4) solution in2:1 acetone:ethanol. Enzyme and resistance domains were subsequentlycoated onto the cellulose acetate butyrate interference domain coatedassembly as described in more detail above. Subsequent testing showedeffective blocking of acetaminophen, a known interferant, at therapeuticlevels. Additionally, at least some sensors (test sensors) were exposedto electron beam radiation at a dose of 25 kGy, while others (controlsensors) were not exposed to electron beam radiation after electron beamsterilization at a dose of 25 kGy, all of which showed equivalentblocking ability of acetaminophen.

Transcutaneous Glucose Sensors with Cellulose Acetate ButvrateInterference Domain and PVP Electrode Domain

In some circumstances, a cellulose acetate butyrate interference domainmay alter or reduce the sensitivity of some glucose oxidase-based sensorassemblies. Accordingly, in some circumstances, it can be useful toapply an electrode domain (e.g., more proximal to the electroactivesurface) of polyvinylpyrrolidone (PVP), or the like, on theelectroactive surface(s) (e.g., working and/or reference electrodes)prior to application of the CAB interference domain. Accordingly, inaddition the above described CAB interference-based sensors, somesensors were coated with 20 wt. % PVP (International Specialty ProductsPVP K-90) solution in DI water prior to the application of CAB and thesubsequent coatings described above. These sensors showed that theaddition of a PVP electrode domain beneath the CAB interference domainresults in an increase in glucose sensitivity (e.g., slope) of thesensor and a reduction of slope variability (e.g., from sensor tosensor).

FIG. 26B is a graph that represents the response of glucose sensors to avariety of interferents. Five sensors were built including a PVPelectrode domain and CAB interference domain as described above andimmersed for at least three minutes in a variety of heated (37° C.) PBSsolutions each containing an interferent as shown in Table 1, below.TABLE 1 Therapeutic Solution Concentration Concentration, InterferentTested, mg/dL mg/dL acetaminophen 6.5 1-2 ascorbic acid 3.8 0.8-1.2dopamine 3.1  0.03-0.104 ibuprofen 40  0.5-2.04 salicylic acid 50 15-30tolbutamide 70 5.3-10  creatinine 30 1.5 uric acid 9.5 7 ephedrine 0.940.005-0.01  L-dopa 1.82 0.02-0.3  methyl dopa 1.735 0.1-0.5 tetracycline0.44 0.4

The graph of FIG. 26B represents data as an average of the five sensorstested in each of the interferent solutions at high concentrations (seecolumn entitled, “Solution Concentration Tested” in Table 1). The y-axisrepresents signal strength in picoAmps after a three-minute immersiontime in each solution. The x-axis represents the interferents tested. Itis noted that at least three interferents showed substantially noresponse (Ascorbic acid, Ibuprofen and Tetracycline). Other interferents(Acetaminophen, Creatinine, Ephedrine, Salicylic acid, Tolazamide,Tolbutamide and Uric Acid) showed minimal response, which is believed toprovide sufficient interferent blocking to enable functional (useful)sensor data even in the presence of these interferents at the testedconcentrations (see FIG. 26C).

FIG. 26C is a graph that represents an apparent glucose concentration or“equivalent glucose signal” caused by each of the interferent solutionsat high concentrations (see column entitled, “Solution ConcentrationTested” in Table 1). For the purposes of calculating the equivalentglucose signal, a sensitivity of 3.5 pA/mg/dL is assumed and the signalstrength converted to an “equivalent glucose signal” (or apparentglucose concentration) in mg/dL. The y-axis represents the equivalentglucose signal in mg/dL. The x-axis represents the interferents tested.As discussed above, at least three interferents showed zero “equivalentglucose signal” (Ascorbic acid, Ibuprofen and Tetracycline). Otherinterferents (Acetaminophen, Creatinine, Salicylic acid, and Tolazamide,showed very minimal signal (or “equivalent glucose signal”); namely,less than about 10 mg/dL “equivalent glucose signal.” An additionalthree of the interferants, (ephedrine, tolbutamide and uric acid) showedminimal signal; namely, less than 20 mg/dl equivalent) which is believedto provide sufficient interferent blocking (resistance) to enablefunctional (useful) sensor data even in the presence of theseinterferents at the tested concentrations. Although three of theinterferents tested showed more response than other of the interferents,these three interferents were re-tested at their therapeuticconcentrations (see column entitled, “Therapeutic Concentration” itTable 1.) After a three-minute immersion time in the therapeuticconcentration, the “equivalent glucose signal” for Dopamine, L-dopa, andMethyldopa, respectively, was measured as 10, 14, and 52 mg/dL.Accordingly, the glucose sensors of the preferred embodimentseffectively block a plurality of interfering species selected with an“equivalent glucose signal” of less than about 30 mg/dL, preferably lessthan about 20 mg/dL, and more preferably less than about 10 mg/dL orless at therapeutic doses of interfering species of the glucose sensor.

The glucose sensors of the preferred embodiments, constructed with acellulose acetate butyrate interference domain, and includingembodiments with a PVP electrode domain, have been shown to block abroad spectrum of exogeneous and endogeneous interferents in therapeuticconcentrations, including, but not limited to, Acetaminophen, Ascorbicacid, Dopamine, Ibuprofen, Salicylic acid, Tolbutamide, Creatinine, Uricacid, Ephedrine, L-dopa, methyl dopa and Tetracycline. Additionally,while some prior art interference domains have been known to createaltered sensitivity of the sensor to glucose (e.g., variability and/orunreliability of sensors in manufacture), the preferred glucose sensorsbuilt with a cellulose acetate butyrate interference domain, andincluding embodiments with a PVP electrode domain, provide excellentglucose sensitivity consistency for sensor manufacture. Furthermore, itwas observed that the preferred embodiments described herein provideglucose sensors that reduce or eliminate break-through upon prolongedexposure to a solution containing an interferant.

Deposition of Resistance Domain Using Physical Vapor Deposition

Twenty nine (29) transcutaneous sensors were fabricated by providing aplatinum wire, vapor-depositing the platinum with Parylene to form aninsulating coating, helically winding a silver wire around the insulatedplatinum wire (to form a “twisted pair”), masking sections ofelectroactive surface of the silver wire, vapor depositing Parylene onthe twisted pair, chloridizing the silver electrode to form a silverchloride reference electrode, and removing a radial window on theinsulated platinum wire to expose a circumferential electroactiveworking electrode surface area thereon, this assembly also referred toas a “parylene-coated twisted pair assembly.” The electroactive surfaceof the radial window of each Parylene-coated twisted pair was thencleaned by surface treatment.

An electrode domain was formed over the electroactive surface areas ofthe working and reference electrodes by dip coating the assembly in anelectrode solution (comprising BAYHYDROL® 123, an aliphaticpolycarbonate urethane resin) and drying. An enzyme domain was formedover the electrode domain by subsequently dip coating the assembly in anenzyme solution (comprising BAYHYDROL® 140AQ, an aliphatic polyesterurethane resin, and glucose oxidase) and drying. A resistance domain wasformed over the enzyme domain using a physical vapor deposition processas described above; namely, by placing twenty nine of the assembliescoated with the electrode and enzyme domains into a vacuum chamber andusing an ultrasonic nozzle to produce a mist of micro-droplets of theresistance domain solution (comprising a blend of CHRONOTHANE®-1020 (apolyetherurethaneurea based on polytetramethylene glycol, methylenediisocyanate and organic amines) and CHRONOTHANE®-H (apolyetherurethaneurea based on polytetramethylene glycol, polyethyleneglycol, methylene diisocyanate, and organic amines)) within the vacuumchamber (solution feed rate 1.5 ml/minute; nozzle power 1.5 watts;solution temperature ambient room temp.; chamber temperature 30° C.;nozzle frequency 120 kHz; chamber gas argon; purge gas pressure 3 psi;solvent physical properties: tetrahydrofuran (boiling point 65-67° C.,vapor pressure 143 mm Hg @ 20° C.) and dimethylacetamide (boiling point164.5° C., vapor pressure 2 mm Hg @ 25° C.)). The contact time with themist within the vacuum chamber was about 36 minutes in duration andincluded 12 spray cycles lasting three minutes each. The resistancedomain was then dried for 1 hr at 50° C., 26” vacuum. After drying, thetwenty nine sensors were tested in vitro to determine their slope (i.e.,glucose sensitivity). The twenty nine sensors had an average slope of4.97 pA/mg/dL, with a standard deviation of 0.55 pA/mg/dL, showing theuse of vapor deposition methods, as described herein, to producefunctional sensors with good consistency and uniformity. Specifically,the manufacturing lot consisted of sensors having in vitro sensitivitieswith a standard deviation of about 11%. Methods for producingmanufacturing lots of sensors can be employed to produce sensorstypically with a standard deviation of less than about 20%, preferablyless than about 18%, more preferably a standard deviation of less thanabout 16%, more preferably still a standard deviation of less than about12%, and most preferably a standard deviation of less than about 8%.

In the above-described method, the morphology of the resistance domainwas controlled by adjusting the solvent evaporation rate of the coatingliquid through chamber temperature and chamber vacuum control to yield asurface with the preferred morphology (e.g., non-smoothness). Namely, incontrast to prior art devices which are fabricated using methodsspecifically adapted to depositing a smooth surface (see, for example,WO/2003-072269-A1 to Leiby et al.), devices of the preferred embodimentfabricated using the above-described method have a resistance domainincluding a substantially non-smooth surface (e.g., a roughness on thesurface that varies in appearance under magnification from asuper-positioning of disc shaped objects, such as coins, to a beadlikesurface) A variety of parameters of the vapor depositionapparatus/process can be adjusted to produce the desired non-smoothmembrane surface; namely, parameters including: feed rate, nozzle power,chamber vacuum, liquid solution temperature (to be sprayed), chambertemperature, purge gas pressure or flow rate, identity of the purge gas,total cycle time, number of cycles, and solvent physical properties canbe altered, and are dependent on one another, to produce desiredmembrane surface properties.

FIG. 27 is a photomicrograph obtained by Scanning Electron Microscopy(SEM) at 350× magnification of a sensor formed as described in theexample above, including vapor depositing the resistance domain onto thesensor. FIG. 27 shows the substantially non-smooth surface of the sensorafter deposition of the resistance domain; namely, FIG. 27 shows aplurality of super-positioned disc-shaped objects, wherein thedisc-shaped objects are a result of the deposition of the resistancedomain. Preferably, the disc-shaped objects are rounded, for example,circular, oval or tear drop-shaped. In this example, the averagediameter of the disc-shaped objects (by either the shortest or longestdimension) is preferably from about 5 to about 250 microns, morepreferably from about 10 to about 100 microns, and more preferably stillfrom about 30 to about 80 microns; however, larger or smaller averagediameters can be desirable in certain embodiments. For example, in onealternative embodiment, certain parameters of the vapor depositionprocess were modified (e.g., temperature), which resulted in smallerdiameter beads (e.g., a speckled appearance) than shown in FIG. 27.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. Pat. No.4,994,167; U.S. Pat. No. 4,757,022; U.S. Pat. No. 6,001,067; U.S. Pat.No. 6,741,877; U.S. Pat. No. 6,702,857; U.S. Pat. No. 6,558,321; U.S.Pat. No. 6,931,327; and U.S. Pat. No. 6,862,465.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. PublicationNo. US-2005-0176136-A1; U.S. Publication No. US-2005-0251083-A1; U.S.Publication No. US-2005-0143635-A1; U.S. Publication No.US-2005-0181012-A1; U.S. Publication No. US-2005-0177036-A1; U.S.Publication No. US-2005-0124873-A1; U.S. Publication No.US-2005-0051440-A1; U.S. Publication No. US-2005-0115832-A1; U.S.Publication No. US-2005-0245799-A1; U.S. Publication No.US-2005-0245795-A1; U.S. Publication No. US-2005-0242479-A1; U.S.Publication No. US-2005-0182451-A1; U.S. Publication No.US-2005-0056552-A1; U.S. Publication No. US-2005-0192557-A1; U.S.Publication No. US-2005-0154271-A1; U.S. Publication No.US-2004-0199059-A1; U.S. Publication No. US-2005-0054909-A1; U.S.Publication No. US-2005-0112169-A1; U.S. Publication No.US-2005-0051427-A1; U.S. Publication No. US-2003-0032874; U.S.Publication No. US-2005-0103625-A1; U.S. Publication No.US-2005-0203360-A1; U.S. Publication No. US-2005-0090607-A1; U.S.Publication No. US-2005-0187720-A1; U.S. Publication No.US-2005-0161346-A1; U.S. Publication No. US-2006-0015020-A1; U.S.Publication No. US-2005-0043598-A1; U.S. Publication No.US-2003-0217966-A1; U.S. Publication No. US-2005-0033132-A1; U.S.Publication No. US-2005-0031689-A1; U.S. Publication No.US-2004-0045879-A1; U.S. Publication No. US-2004-0186362-A1; U.S.Publication No. US-2005-0027463-A1; U.S. Publication No.US-2005-0027181-A1; U.S. Publication No. US-2005-0027180-A1; U.S.Publication No. US-2006-0020187-A1; U.S. Publication No.US-2006-0036142-A1; U.S. Publication No. US-2006-0020192-A1; U.S.Publication No. US-2006-0036143-A1; U.S. Publication No.US-2006-0036140-A1; U.S. Publication No. US-2006-0019327-A1; U.S.Publication No. US-2006-0020186-A1; U.S. Publication No.US-2006-0020189-A1; U.S. Publication No. US-2006-0036139-A1; U.S.Publication No. US-2006-0020191-A1; U.S. Publication No.US-2006-0020188-A1; U.S. Publication No. US-2006-0036141-A1; U.S.Publication No. US-2006-0020190-A1; U.S. Publication No.US-2006-0036145-A1; U.S. Publication No. US-2006-0036144-A1; and U.S.Publication No. US-2006-0016700A1.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. applicationSer. No. 09/447,227 filed Nov. 22, 1999 and entitled “DEVICE AND METHODFOR DETERMINING ANALYTE LEVELS”; U.S. application Ser. No. 11/280,672filed Nov. 16, 2005, and entitled “TECHNIQUES TO IMPROVE POLYURETHANEMEMBRANES FOR IMPLANTABLE GLUCOSE SENSORS”; U.S. application Ser. No.11/280,102 filed Nov. 16, 2005, and entitled “TECHNIQUES TO IMPROVEPOLYURETHANE MEMBRANES FOR IMPLANTABLE GLUCOSE SENSORS”; U.S.application Ser. No. 11/201,445 filed Aug. 10, 2005 and entitled “SYSTEMAND METHODS FOR PROCESSING ANALYTE SENSOR DATA”; U.S. application Ser.No. 11/335,879 filed Jan. 18, 2006 and entitled “CELLULOSIC-BASEDINTERFERENCE DOMAIN FOR AN ANALYTE SENSOR”; U.S. application Ser. No.11/334,876 filed Jan. 18, 2006 and entitled “TRANSCUTANEOUS ANALYTESENSOR”; U.S. application Ser. No. 11/333,837 filed Jan. 17, 2006 andentitled “LOW OXYGEN IN VIVO ANALYTE SENSOR”.

All references cited herein, including but not limited to published andunpublished applications, patents, and literature references, and alsoincluding but not limited to the references listed in the Appendix, areincorporated herein by reference in their entirety and are hereby made apart of this specification. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention.

1. A system configured to control use of a medical device, the systemcomprising: a reusable device and at least one single-use device, thesingle-use device being associated with the reusable device; and ahardware key comprising a memory with information stored therein,wherein the hardware key is configured to operatively connect to thereusable device and to transmit at least a portion of the information tothe reusable device.
 2. The system of claim 1, wherein the hardware keyis a dongle.
 3. The system of claim 1, wherein the hardware keycomprises a license comprising information selected from the groupconsisting of manufacturing information, calibration information,identification information, expiration information, durationinformation, insertion information, and combinations thereof.
 4. Thesystem of claim 3, wherein at least some of the information is encryptedin the memory of the hardware key.
 5. The system of claim 1, wherein thereusable device is configured to authenticate the hardware key uponoperative connection thereto.
 6. The device of claim 1, wherein thereusable device is configured to read information from the hardware key.7. The system of claim 1, wherein the reusable device is configured tomark or erase at least a portion of the information in the memory of thehardware key to ensure the hardware key is used only a predeterminednumber of times.
 8. The system of claim 7, wherein the reusable deviceis configured to mark or erase at least a portion of the information inthe memory of the hardware key to ensure the hardware key is used onlyonce.
 9. The system of claim 1, wherein the reusable device comprises areceiver, wherein the single-use device comprises at least one analytesensor, and wherein the receiver is configured to receive, process, ordisplay data from the analyte sensor.
 10. The system of claim 9, whereinthe receiver is configured to control an amount of time over which datais obtained from the analyte sensor responsive to receipt of informationfrom the hardware key.
 11. The system of claim 1, wherein the hardwarekey is configured to physically connect to a port on the reusabledevice.
 12. The system of claim 1, wherein the medical device comprisesan implantable glucose sensor system, wherein the reusable devicecomprises a receiver, and wherein the single-use device comprises atranscutaneous glucose sensor.
 13. The system of claim 12, wherein thehardware key is packaged with the one or more transcutaneous glucosesensors, and wherein the hardware key is configured to limit theduration of or number of insertions of the one or more transcutaneousglucose sensors.
 14. A method of limiting use of a medical device, themethod comprising: providing a hardware key associated with a single-usedevice, wherein the hardware key is configured to control an amount oftime over which data is obtained from the single-use device; andproviding a reusable device comprising a port for connecting thehardware key thereto.
 15. The method of claim 14, further comprisingconnecting the hardware key to the reusable device.
 16. The method ofclaim 14, further comprising transmitting encrypted information from thehardware key to the reusable device.
 17. The method of claim 16, whereinthe transmitting step comprises transmitting at least one ofmanufacturing information, calibration information, identificationinformation, expiration information, duration information, and insertioninformation.
 18. The method of claim 14, further comprisingauthenticating the hardware key upon operative connection to thereusable device.
 19. The method of claim 14, further comprising readinginformation from the hardware key upon operative connection to thereusable device.
 20. The method of claim 14, further comprising markingor erasing at least a portion of the information from the hardware keyafter the step of reading information from the hardware key to ensurethe hardware key is used only a predetermined number of times.
 21. Themethod of claim 20, wherein the marking or erasing step comprisesmarking or erasing at least a portion of the information from thehardware key to ensure the hardware key is used only one time.
 22. Themethod of claim 14, wherein the reusable device comprises a receiver,and wherein the receiver receives, processes, or displays data from thesingle-use device.
 23. The method of claim 14, wherein the medicaldevice comprises an implantable glucose sensor system, wherein thereusable device comprises a receiver, and wherein the single-use devicecomprise a transcutaneous glucose sensor.
 24. The method of claim 23,wherein the hardware key is configured to limit a duration of insertionor a number of insertions of the transcutaneous glucose sensor.
 25. Asensor system configured to measure an analyte concentration in a host,the system comprising: at least one sensor configured to be implanted ina host and configured to measure an analyte concentration in a tissue ofthe host; a receiver operatively connectable to the sensor andconfigured to provide analyte data representative of an analyteconcentration in the host; and a hardware key configured to connect tothe receiver, wherein the hardware key comprises information selectedfrom the group consisting of manufacturing information, calibrationinformation, identification information, expiration information,duration information, insertion information, and combinations thereof.26. The sensor system of claim 25, further comprising packagingconfigured to contain the sensor and the hardware key.
 27. The sensorsystem of claim 25, wherein the hardware key is programmed with alicense code.
 28. The sensor system of claim 27, wherein the licensecode comprises information configured to control a duration of insertionor a number of insertions of the sensor.